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THE  LIBRARY 

OF 

THE  UNIVERSITY 

OF  CALIFORNIA 

LOS  ANGELES 

GIFT  OF 


SAN  FRANCISCO 
COUNTY  MEDICAL  SOCIETY 


THE  BIOLOGY  AND  TREATMENT  OF 
VENEREAL    DISEASES. 


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Plate  1. — Frontispiece. 


»  '  J       '  I  ' 


VENEREAL  DIS.  ^^^^ 


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'"!  I  I.  ., 


Plate    1. — Section    of  a  Syphilitic   Lymphatic   Gland,  showing   the 

VARIOUS   PHASES    OF   THE    LEVCOCYTOZOON   SYPHIUDIS,  STAINED    WITH 

Pyronin  and  Methyl  Greek. 

A.  Binary  fissioa  of  zygote. 

B.  Female  gamete  just  after  fertilisation. 

C.  Spore  cyst. 

D.  Developing  male  gametocyte  in  large  mononuclear  leucocyte. 

E.  Spirochaetal  coil  in  large  mononuclear  leucocyte. 

F.  Spore  cyst. 

G.  Spirochaetal  coil. 

H.  Developing  meiozoites  in  endothelial  cell. 

J.  Female  gamete. 

K.  Developing  trophozoite  in  conncotivo-ti«sue  cell. 

L.  Ditto,  earlier  stage. 

M.  Female  gametocytes. 


Fronlinpiere. 


THE 


'249 


BIOLOGY  AND  TEEATMENT 


VENEREAL  DISEASES 


AND   THE 


BIOLOGY  OF  INFLAMMATION  AND  ITS 
RFLATIONSIIIP  TO  MALIGNANT  DISEASE 


BY 


J.  E.  R.  McDONAGH,  F.R.C.S. 

SURGEON    TO    OTJT-PATIENTS,   LONDON    LOCK    HOSPITAL,    ETC. 


LEA    &    FEBIGER 

PHILADELPHIA    AND    NEW   YORK 

191  (j 


Biomed'cil 
Likraiy 

CONTENTS. 


Part  I. 
THE    BIOLOGY    AND    TREATMENT    OF    VENEREAL    DLSEASES. 

CHAPTEE.  PAGE. 

L     History  of  the  Organism  of  Syphilis          ...         ...         ...         ...         ...         ...  1 

IL     The  Life-Cycle  of  the  Organism  of  Syphilis  (ieMcocj/fozoow  (SypMidis)            ...  8 

III.  Aberrant  Development  of  the  Life-Cycle  and  Cocc/fZjosJs  ^I'enerea      ...         ...  11 

IV.  Errors  to  be  avoided  in  examining  Syphilitic  or  other  material     ...          ...  21 

V.     Arguments  against  ieucocj/tozooft  (Syy/ji7irfis        ...         ...         ...         ...         ...  23 

VI.     Chemistry  of  the  Leucocylozoon  Syphilidis           ...         ...         ...         ...         ...  25 

VII.     The  Light  which  the  Chemistry  of  the  Leucocylozoon  Syphilidis  flirows  upon 

previously  unexplamcd  phenomena   ...         ...         ...         ...         ...         ...  55 

VIII.     Tlie  cultivation  of  the  Spirochaeta  Pallida  and  the  methods  of  demonstrating 

this  Organism    ...         ...         ...         ...         ...         ...         ...         ...         ...  59 

IX-.     Technique  of  the  Wassermann  Reaction  ...         ...         ...         ...         ...          ...  G5 

X.     The  Rationale  or  Modus  operandi  of  the  Wassermann  Reaction  and  Abder- 

halden's  Test 09 

Xl^-^riie  significance  of  the  Wassermann  Reaction  and  the  way  in  which  it  is 

influenced  by  treatment          ...         ...         ...         ...         ...         ...         ...  100 

XIL     The  Cutireaction       113 

XIII.     The  Biology  of  the  various  stages  of  Syphilis      ...          ...          ...          ...          ...  119 

XIVA  The  Cbnical  Aspect  of  the  SyphiUtic  Cutaneous  Lesions            ...         ...         ...  124 

XV.     SyphiUs  of  the  Lympho- and  Hacmopoetic  Systems      ...         ...         ...         ...  144 

XVI.     SyphUis  of  the  Male  Genito-urinary  Tract            152 

XVn.     SyphiUs  of  the  Eyes  and  Ears         ■      ...  155 

XVIIL     Syphilis  of  the  Mouth  and  Throat              162 

XIX:     Syphilis  of  the  Bronchi  and  Lungs             ...         ...          ...         ...          ...         ...  166 

XX.     Syphilis  of  the  Bones  and  Joints    ...         ...         ...         ...         ...         ...         ...  169 

XXI.     SyphiUs  of  the  Abdominal  Viscera 174 

XXII.     Esamination  of  the  Cerebro-SpLnal  Fluid 182 

XXin.     The  Biology  of  SyphiUs  of  the  Nervous  System 200  1 

XXIV.     The  Clinical  Aspect  of  Syphilis  of  the  Nervous  System 231 

XXVt     SyphiUs  in  Women 248 

XXVL     Congenital  SyphiUs 260 

XXVII.     Chemotherapy  and  its  mode  of  action  in  the  case  of  Syphilis 276 

XXVIII.     Toxic  Symptoms  of  Salvarsan  and  Neo-salvarsan           294 

XXIX.     The  Treatment  of  Syphilis 321 

XXX.     Drugs  LTsed  in  the  Treatment  of  Syphilis  and  the  Methods  of  administering 

them        337 

XXXL     CTctM- J/oHe  (Soft  Sore)         358 

XXXIL     Gonorrhoea '.         ...  371 


60349S 


(    vi    ) 
Contents — cnntiii  ncrl. 

CHAPTER.  PAGE. 

XXXIII.     Comiilications    of    Urethritis    Gonorrhoica    due    to   direct   extension   of    the 

Organism  ...  ...  ...  ...  ...  ...  ...  ...  ...  388 

XXXIV.     Complications  of  Gonorrhoea  due  to  a  spread  by  Metastasis  of  the  Organism  406 

XXXV.     Non-Gonococcal  Urethritis  ...         ...         ...         ...         ...         ...         ...         ...  416 

XXXVI.     Gonorrhoea!  Diseases  of  the  Eyes 420 

XXXVII.     Gonococcal  Rashes 424 

XXXVIII.     Gonorrhoea  in  Women  ...  ...         ...         ...  ...         ...  ...         ...  427 

XXXIX.     The  Treatment  of  Gonorrhoeal  Infections  by  Vaccines  and  the  Application 

of  the  Complement  fixation  test  in  Gonorrhoea       ...         ...         ...         ...  435 

XL.     Phimosis, and  Paraphimosis...         ...         ...         ...         ...         ...         ...         ...  401 

XLI.     Balanitis,   Condyloma  Acuminatum,    Molluscum   Contagiosum,  Herpes  Geni- 
talis,  Granuloma   Inguinale,   Induratio    Penis    Plaslica,   and    Pediculosis 

Pubis       ...         ...         ...         ...         ...         ...         ...         ...         ...  ...  464 

XLII.     Sexual  Neurasthenia...  ...         ...  ...  ...  ...         ...  ...  ...  478 

XLIII.     Venereal  Disease  and  Marriage       485 

XLIV.     Venereal  Disea.se  and  Public  Health  493 

Part    II. 

THE  BIOLOGY  OF  INFLAMMATION  AND  ITS  RELATIONSHIP  TO 
MALIGNANT    DISEASE. 

Introduction  ...  ...  ...  ...  ...  ...  ...  ...  ...  ...     49'J 

XLV.     The  Role  played  by  an  Epithelial  Cell  in  Inflammation  and  its  probable 

relationship  to  Malignant  Epithelioma  ,     ...         ...         ...         ...         ...     501 

XLVI.     The  Role  played  by  a  Lymphocyte  in  Inflammation  and  its  probable  relation- 
ship to  Sarcoma  ...         ...         ...         ...         ...         ...         ...         ...     520 

XL VII.     The  Role  jjlayed  by  an  Endothelial  Cell  in  Inflammation  and  its  probable 

relationship  to  Sarcoma  ...  ...  ...  ...  ...  ...         ...     563 

XLVIII.     The  Role  played  by  other  Oells  in  Inflammation  and  their  probable  relation- 
ship to  Malignant  Disease        580 


ILLUSTRATIONS. 


Part  I. 

Plate    1  (coloured). — Phases  of  the  Leucocylozoon  si/philidis  in  section     ...     Frontispiece. 
Plate    2. — Schematic  representation  of  the  jiliases  of  the  Leucocylozoon  syjMlidis 

Facing  page         8 
Plates  3-11. — Photographs  (X  1,500)  of  the  phases  of   the  Lencoojiozoon  syphilidis 

Facing  page       10 
Plate  12    (coloured). — 1.  Developing    trophozoite   in    a    vessel    in    the    cerebral   cortex. 
2.  Development  of  the  male  gametocyte  in  a  late  cutaneous  syphilide 

Facing  2'('9^       ^^ 
Plate  13    (coloured). — 1.  Polar  body  formation  in  a  chancre.     2.  Spore  cyst  in  a  vessel 

wall  Facing  page       10 

Plate  14. — Aberrant  development  of  the  ieacocy/ozoon  syphilidis     ...         ...    Facing  page       12 

Plate  15. — ^Low  power  section  of  a  papule  from  a  case  of  Coccidiosis  avenerea  „         .,         18 

Plate  16-17. — Photographs  (X  1,500)  of  the  phases  of  the  avenereal  cocoidium  „         ,,         18 

Plate  18  (coloured). — High  power  section  of  a  pajiule  from  a  case  of  Coccidiosis  avenerea, 

showing  the  parasitic  phases      Facing  page       18 

Plate  19. — Bodies  seen  in  vivo,  when  examining  fresh  tissue,  stained  with  borax  methylene 

blue  Facing  imge       20 

Plate  20. — Various  forms  of  the  aminoplasma  cells  as  seen  in  in  vivo  staining. . .    Facing  page      22 
Plate  21. — Photographs  (X  1,500)  of  lymphocytes  developing  in  endothelial  ccUs 

Facing  page       22 
Plate  22  (coloured). — Twelve  methods  for  differentiatmg  the  phases  of  the  Leucocylozoon 

syphilidis  in  section 
Plate  23. — Aminoplasma  cells  as  seen  in  sections 
Plate  24  (coloured). — Section  specially  treated  to  show  only  the  phases  of  the  Leucocylozoon 

syphilidis   ... 
Plate  25  (coloured). — Papulo-erosive  chancre 

Plate  26  (coloured). — Papulo-erosive  chancre  on  the  skin  of  the  penis 
Plate  27  (coloured). — Painilo-crosive  chancre  in  corona 
Plate  28  (coloured). — Papulo-erosive    chancre    on    the    under    surface    of 

Plate  29  (coloured). — A  chancre  of  the  frocnum  ...         ... 

Plate  30  (coloured). — ^A  chancre  in  one  of  the  furrows  of  the  prepuce 
Plate  31  (coloured). — A  papulo-ulcerative  chancre 

Four  diagrams  of  the  early  syphihtic  skin  lesions  ... 

Diagrammatic  representation  of  the  origin  of  syphilitic  alopecia 

Two  diagrams  of  the  recurrent  syphilitic  skin  lesions 
Plate  32  (coloured). — Diffuse  pajiular  syphilitic  eruption  on  the  genitals 

Four  diagrams  of  the  recurrent  syphilitic  skin  lesions 

Barker's  lumbar  puncture  needles     ... 


Facing  page 

30 
34 

Leucocylozoon 

Facing  page 

40 
124 

126 

128 

the    prepuce 
Facing  page 

130 
132 

134 

., 

134 

. . .     Page 

135 
137 

,, 

138 

Facing  page 
. . .     Page 

138 
139 
182 

(     viii     ) 

Illustrations — continued. 

Plate  33. — 1.  (Coloured)  Female  gametocyte  in   the  pia-arachnoid.     2.  Schematic  repre- 
sentation of  the  phai?es  of  the  icucoci/Zozoo?!  sj/^/iiZirfi.s         ...    Fachxg jjage  210 
Two  diagrams  of  McDonagh's  sjrringe          ...         ...         ...         ...         ...    Page  343 

Plate  34  (coloured). — A  single  soft  sore...         ...         ...         ...         ...         ...    Facing  page  358 

Plate  35. — 1.  Low  power  section  of  the  soft  sore  depicted  on  Plate  34.     2.  Higher  power 

section  of  the  same  sore  ...         ...         ...         ...         ...         ...    Facing  page  358 

Plate  36  (coloured). — Higher  power  section  still  of  sore  depicted  on  Plate  34,  showing 

the  streptobacillus  ...         ...         ...         ...         ...         ...    Facing  page  358 

Plate  37  (coloured). — Ulcus  molle  elevatum  ,,         „  360 

Plate  38. — 1.  Low  power  section  of  sore  depicted  on  Plate  37.     2.  Higher  power  section 

of  the  same  sore  ...         ...         ...  ...         ...         ...         ...    Facing  page  360 

Plate  39  (coloured). — Ulcus  molle  serpiginosum  ...         ...         ...         ...         ...  ,,         ,,  362 

Plate  40. — Section  of  Ulcus  molle  serpiginosum ...         ...         ...         ...         ...  „        ,,  362 

Plate  41  (coloured). — Keralodermia  blennorrhagica        ...         ...         ...         ...  ,,         „  424 

Plate  42  (coloured). — Section  of  Qranuloma  inguinale,  showing  the  phases  of  its  causative 

organism    ...         ...         ...         ...         ...         ...         ...         ...    Facing  page  472 

Part    II. 

Plate  43  (coloured). — 1.  Section  of  a  malignant  prickle-celled  epithehoma,  stained  with 
pyronm  and  methyl  green.  2.  Same  tissue  stained  with  EhrUch's 
triacid  mixture     ...         ...         ...         ...         ...         ...         ...    Facing  page    500 

Plate  44  (coloured). — Pseudo-parasitic   bodies   from   a   case   of    malignant   prickle-ceUed 

epithelioma  ...         ...         ...         ...         ...         ...         ...    Facing  page     506 

Plate  45. — 1.  Section  of  a  milium.     2.  Trichoepdtlielioma  papulosum  ...  „         ,,       514 

Plate  46. — A  section  of  a  rodent  ulcer,  showing  presence  of  a  sebaceous  adenoma  and  a 

milium       ...         ...         ...         ...         ...         ...         ...         ...    Facing  page    514 

Plate  47. — 1.    Section    of    a    sjTingoma.      2.    SjTuigoma    with     trichoepitheliomatous 

elements     ...         ...         ...         ...         ...         ...         ...  ...    Facing  page     518 

Plate  48. — Syringoma         ...         ...         ...         ...         ...         ...         ...         ...  .,         .,       518 

Plate  49. — A   mixed   tumour,    showing   simultaneous   appearance   of   trichoepithehoma, 

sebaceous  adenoma  and  syringoma      ...         ...         ...         ...    Facing  page    518 

Pl.ate  50  (coloured). — 1.  Crystalline  form  of  aminoplasma  cells.     2.  Section  of  a  lymphatic 

gland  from  a  rat,  which  died  of  sleeping  sickness...         ...    Facing  page     532 

Plate  51  (coloured). — Three  sections  taken  from  different  cases  of  intermediary  lymphatic 
aleucaemic  lymphocytomata,  showing  the  changes  from  the  innocent  to 
the  malignant  form         Facing  page    552 

Plate  52  (coloured). — 1.  A  section  from  a  recurrent  case  of  intermediary  cutaneous    aleu- 
caemic lymphooytoma,  following  X-rays.     2.  A  section  of  a  sarcomatous 
ulcer  (plasmo-sarcomatosis)       ...         ...         ...         ...         ...    Facing  page    554 

Plate  53. — Sections  from  a  case  of  Naevo-xantho-endothelioma  taken  at  various  periods 

during-its  metamorphosis  ...         ...         ...         ...         ...    Facing  page     568 

Plate  54. — Sections  from  cases  of  Naevo-xantho-endothehomata       ...         ...  ,,         „       572 


Part  I. 

THE    BIOLOGY    AND    TREATMENT    OF   VENEREAL 

DISEASES. 


CHAPTER  I. 
HISTORY  OF  THE   ORGANISM   OF  SYPHILIS. 

Several  observers  described  what  they  considered  to  be  the  cause  of  syphilis, 
but  none  attracted  much  attention  until,  in  the  year  1884,  Lustgarten^  described 
a  bacillus  which  resembled  the  tubercle  bacillus.  Koch  had  discovered  the  tubercle 
bacillus  two  years  previously,  and  at  that  time  the  opinion  was  widely  held  that 
sjnphilis  and  tuberculosis  were  closely  related  to  each  other  ;  therefore  Lustgarten's 
work  was  eagerly  received,  and  was  quickly  confirmed  from  several  sources. 

Belief  in  Imstgarten's  theory  was,  however,  short  lived,  as  in  a  year  or  two's 
time,  first  Alvarez  and  Favel,^  then  Klemperer,^  and  many  others  showed  that  the 
bacillus  described  was  probably  only  the  smegma  bacillus. 

During  the  next  few  years,  certain  cocci,  granules,  etc.,  were  brought  forward 
in  turn  as  the  casuative  agents  of  syphilis,  but  confirmation  was  lacking. 

The  next  in  the  field  was  van  Niessen,*  with  his  Syphilomyces,  a  polymorphic 
bacillus  which  he  succeeded  in  culturing  from  the  blood  of  syphilitic  patients. 
After  the  Spirochaeta  pallida  had  been  discovered,  van  Niessen  stated  that  he 
believed  the  latter  was  a  developmental  form  of  his  bacillus. 

That  the  pathogenic  agent  of  syphihs  -was  a  protozoon,  was  first  suggested  by 
Doehle,^  who  described  movable,  flagellated  protoplasmic  bodies,  in  the  secretion 
from  chancres,  in  the  tissue  juice  of  congenital  syphilitic  organs,  and  in  the 
blood. 

Then  Clarke,®  Schiiller,'  ^and  others  described  protozoa,  which  they  took  to  be 
the  syphilitic  organism. 

Although  they  did  not  describe  any  organism,  Metschnikofi  and  Roux,'^" 
in  1903,  made  the  important  discover)^  that  apes  could  be  inoculated  with  syphilis, 
and,  in  the  following  year,  Klingmiiller  and  Baermann^^  showed  that  the   syphilitic 

A 


2  THE   BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

virus  would  not  pass  through  a  filter,  and,  therefore,  that  the  cause  was  not  an 
ultramicroscopic  organism. 

Soon  after  these  two  very  important  observations  had  been  made,  Siegel^^  ^^ 
came  forward  with  his  Cytorrhydes  luis.  The  name  cytorrhyctes  was  used,  because 
Siegel  found  that  his  bodies  closely  resembled  bodies  which  Guarnieri  had  discovered 
in  small-pox,  and  had  called  cytorrhyctes. 

Some  of  the  bodies  which  Siegel  described  were  actively  motile, 0'5 to  25  n  in 
diameter,  and  were  easily  distinguished  from  other  structures  by  their  powerful 
refractility :  others  were  bodies  which  Siegel  later  called  spores,  containing  2  to  16 
nuclei. 

Although  Siegel's  work  received  confirmation,  it  passed  into  obHvion  when 
Schaudimi  and  E.  Hofimann^*  published  their  joint  paper  on  an  organism  named 
by  them  the  Spirochaeta  pallida.  No  sooner  had  the  Sjnrochaeta  pallida  been 
discovered,  than  one  paper  appeared  after  another  confirming  Schaudinn  and 
Hofltmann's  discovery. 

At  the  Pasteur  Institute  in  Paris,  Metschnikoft'  and  Roux*  ^^  found  the 
Spirochaeta  pallida  in  the  lesions  they  produced  by  inoculating  chimpanzees  with 
human  syphilitic  material :  and  Levaditi,  by  means  of  silver  nitrate  impregnation, 
succeeded  in  demonstrating  the  Spirochaeta  pallida  in  sections  of  congenital  syphihtic 
organs. 

So  many  observers  took  up  this  work  that,  in  a  very  short  time,  the  Spirochaeta 
pallida  had  been  found  in,  broadly  speaking,  every  known  type  of  syphihtic  lesion. 

While  searching  for  the  Spirochaeta  pallida,  many  other  spirochaetae  were 
observed,  and  at  one  tune  there  was  a  great  discussion  as  to  whether  these  extraneous 
spirochaetae  were  distinct  organisms,  or  whether  they  were  aberrant,  or  even 
developmental  forms  of  the  Spirochaeta  pallida. 

The  other  spirochaeta  to  which  most  attention  was  directed,  was  the  Spirochaeta 
refringens,  and  many  well-trained  observers  stated  that  they  had  found  it  only  in 
syphilitic  material,  in  company  with  the  Spirochaeta  pallida.  TQis  valuable 
observation  was,  I  believe,  somewhat  unjustifiably  set  aside,  and  the  Spirochaeta 
refringens  was  stated,  both  to  be  utterly  imrelated  to  the  SpirocJuieta  pallida,  and 
to  be  unspecific  for  syphihs. 

At  first  the  Spirochaeta  pallida  was  generally  considered  to  be  a  protozoon. 
Others  held  that  it  belonged  to  the  bacteria,  an  opinion  which  Meirowsky^^  has  lately 
strenuously  attempted  to  maintain.  Dobell^'  also  holds  the  view  that  spirochaetae 
are  vegetable  organisms,  but  the  Spirochaeta  pallida  was  not  amongst  the  spirochaetae 
studied  by  him. 

The   third    opinion    was  that  the  spirochaetae  held  a  position  of  their  own, 


THE    HISTORY   OF   THE    ORGANISM.  3 

midway  between  the  bacteria  and  the  protozoa  ;   and  most  elaborate  families  and 
sub-families  were  drawn  up,  to  include  all  the  known  forms. 

Meirowsky^*  describes  branching,  with  chib  formation  occurring  at  the  end  of 
the  branches,  in  fact  in  almost  any  part  of  the  Spirochaeta  pallida.  These  branches 
appear  to  resemble  the  mycelium  and  spores  seen  in  fungi,  and  he  suggests  therefore 
that  the  syphilitic  organism  belongs  to  the  class  including  the  leprosy  and  tubercle 
baciUi. 

Summarising  his  views,  Meirowsky  states  that  the  absence  of  a  nucleus,  of  an  un- 
dulating membrane,  and  of  a  blepharoplast,  are  strong  arguments  against  the  Spiro- 
chaeta pallida  being  a  protozoon.  That  the  Spirochaeta  pallida  divides  transversely, 
is,  according  to  him,  also  no  proof  that  it  is  a  protozoon,  since  transverse  fission  is 
the  general  method  of  dividing  in  bacteria.  Finally,  Meirowsky  states,  that  "  it  is 
mere  waste  of  time  to  elaborate  analogies  between  spirochaetae,  and  the  flagellata, 
or  other  protozoa  with  sexual  differences,  and  reproductive  cycles."  I  find  myself 
unable  to  agree  with  Meirowsky,  and  his  last  statement  is,  in  itself,  sufficient  to  throw 
considerable  doubt  upon  the  value  of  his  work. 

With  one  or  two  exceptions,  the  Spirochaeta  pallida,  as  has  already  been  stated, 
was  universally  accepted  as  the  cause  of  syphihs  ;  but  de  Korte,i^  who  worked  at 
the  London  Lock  Hospital  for  some  time,  was  strongly  opposed  to  the  general  view. 
Although  the  illustrations  accompanying  de  Korte's  paper  are  not  good,  there  can 
be  little  doubt  that  some  of  the  bodies  described  are  the  same  as  Siegel's  spore  cysts. 

In  his  last  article,  Hoffmann^''  states  very  positively  that  the  Spirochaeta  pallida 
is  the  sole  cause  of  syphihs.  The  result  of  this  is,  that  no  disciple  of  Hoft'mann  has 
repeated  any  of  the  work  which  has  been  done  to  prove  the  existence  of  a  hfe-cycle 
of  this  organism.  Naturally,  Hoffmann  and  his  disciples  consider  the  existence  of 
the  life-cycle  to  be  fundamentally  impossible. 

If  the  Spirochaeta  pallida  is  the  sole  cause  of  syphihs,  it  is  difficult  to  explain 
why  the  incubation  period  of  syphihs  is  so  long,  why  division  is  not  seen  in  every 
specimen  examined,  and  why  one  or  two  injections  of  salvarsan  do  not  always 
effect  a  cure.  ^ 

I  was  aware  that,  in  most  known  protozoal  diseases,  the  organism  had  several 
phases,  and  that  recurrences  of  the  diseases  were  common.  I  was  also  aware  of  the 
similarity  between  syphilis  and  malaria.  In  the  fight  of  these  facts,  it  occurred  to 
me,  in  191 1,  that  the  obscure  points  in  syphihs,  connected  with  the  Spirochaeta  pallida, 
could  be  cleared  up,  only  if  the  spirochaeta  itself  could  be  regarded  as  merely  a  phase  ^ 
in  the  life  history  of  some  unknown  protozoon. 

Seeing  that  svphilis  could  be  conveyed  from  person  to  person,  there  was  no 
reason  to  assume  that   an  intermediary  host  was  required,  as  is,  for   instance,  the 

a2 


4  THE   BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

case  in  malaria.  Therefore,  if  there  were  other  phases,  I  expected  to  fuid  them  all 
in  the  patient  himself. 

Owing  to  the  motiUty  of  the  Spirochaeta  2Mttida,  and  to  its  resemblance  to  a 
spermatozoon  and  to  the  male  gametes  of  the  various  protozoa,  it  occurred  to  me  that 
perhaps  it  was  the  adult  male  body  of  a  protozoon.  My  chief  reason  for  thinking 
that  the  Spirochaeta  pallida  was  an  end  phase,  was  the  fact  that,  in  spite  of  the 
numerous  examinations  which  I  had  made  of  spirochaetal  tissue,  I  had  never 
succeeded  in  seeing  the  organism  divide. 

It  had  been  suggested,  some  time  previously,  that  the  Spirochaeta  jmllida  had 
a  resting  stage — in  fact,  Schaudinn  was  at  work  on  this  very  point  just  prior  to  his 
untimely  death. 

V.  Prowazek^^  was  under  the  impression  that  the  Spirochaeta  pallida  rolled  up 
into  a  ball.  Similar  circular  bodies  were  also  found  by  Hoffmann,^''  in  the  spleen  of 
a  congenital  syphilitic,  and  intermediate  stages  in  unrolhng  and  rolling-up  were 
described  by  him.  The  resting  stage,  as  just  described,  was  held  to  be  responsible 
for  the  long  incubation  period  of  svphilis.  Kryzsztalowicz  and  Siedlecki^^  '-'*  described 
a  sexual  development,  and  in  that,  short,  thick,  nucleated  bodies,  which  the}'  looked 
upon  as  macrogametes,  gave  rise,  by  a  process  of  division,  to  microgametes ;  but 
these  authors  afterwards  altered  their  views. 

As  a  result  of  my  investigations,  I  am  firmly  of  the  opinion  that  the  organism 
of  syphilis  has  a  sexual  development,  but  different  from  that  just  described.  Full 
details  of  my  work  will  form  the  matter  of  the  next  chapter. 

Within  the  last  two  or  three  years  Balfour, ^^  Fry,^^  Kanken,^^  and  others  have 
described  a  granular  stage  in  the  development  of  certain  spirochaetae  and  try- 
panosoraes,  which  they  have  called  the  "  infective  granule." 

Balfour,  working  with  infected  chickens  (spirochaetosis),  in  which  a  natural 
crisis  had  occurred,  or  in  which  an  artificial  crisis  had  been  induced  by  salvarsan, 
found,  by  use  of  the  dark  ground  illumination,  that  the  spirochaetae  broke  up  into 
granules.  Whether  the  granule  described  by  Balfour  is  the  same  phenomenon 
as  the  bulbous  extremity  of  the  Spirochaeta  pallida,  first  described  by  Herxheimer,^* 
is  not,  however,  clear. 

Henry^*  has  described  the  infective  granule  as  the  initial  phase  in  the  life 
history  of  a  haemogregarine,  which  maj'  or  may  not  be  the  same  as  that  described 
by  Balfour  in  the  spirochaetosis  of  Sudanese  fowls,  and  by  Fry  and  Eanken  in 
certain  trypanosomes. 

These  so-called  "  infective  granules,"  especially  as  described  by  Balfour, 
owing  to  their  close  similarity  to  cell  detritus,  require  fiu'ther  study  before  authori- 
tative statements  can  be  made  about  them. 


THE    HISTORY   OF   THE    ORGANISM.  5 

One  wonders  whether  these  granules  are  the  same  as  the  knobs  occurring  on 
the  branches  of  the  Spirochaeta  pallida,  described  by  Meirowsky.  If  so,  then  the 
opinions  of  Lipschiitz^*  and  Kreibich**  must  be  taken  into  consideration.  Both 
these  observers  maintain  that  Meirowsky's  figures  are  the  results  of  chemico-physical 
changes,  which  have  taken  place  in  the  organism,  probably  of  the  nature  of  a  lipoid 
degeneration. 

There  are  many  pathological  conditions  in  man  caused  by  spirochaetae,  which 
differ  at  once  from  syphilis,  because  they  are  very  amenable  to  treatment,  and 
they  do  not  tend  to  recur. 

Therefore,  it  is  only  reasonable  to  expect  that  there  is  a  difference  in  the 
development  between  the  Spirochaeta  balanitidis,  for  instance,  and  the  Spirochaeta 
pallida . 

The  infective  granule,  described  by  Henry,  is  probably  the  trophozoitic  stage 
of  the  protozoon.  Even  if  this  infective  granule  be  proved  to  be  the  cause  of  certain 
spirochaetal  diseases,  recurrent  fever  and  yaws,  for  example,  it  would  not  necessarily 
follow  that  the  protozoon  causing  syphiHs  had  a  similar  development.  Relapsing 
fever  and  yaws  respond  very  rapidly  to  treatment  with  salvarsan,  whereas  syphilis 
shows  a  strong  tendency  to  recur,  in  spite  of  such  treatment.  These  two  facts 
strongly  suggest  that  the  parasite  of  s3rphiUs  has  some  developmental  form,  of  far 
greater  resistant  capacity  than  that  found  in  relapsing  fever  or  yaws. 

In  December,  1911,  I  began  to  examine  lymphatic  glands  from  the  region 
draining  the  site  of  the  initial  lesion.  These  glands  had  been  removed  early  in  the 
generalisation  stage. 

In  .January,  1912,  I  found  some  bodies  which  I  thought  might  be  parasitic 
in  nature.  These  bodies  had  special  staining  properties,  and  could  not  be  demon- 
strated in  the  control  material.  In  October,  1912,2^  I  published  my  first  paper  on 
the  life  history  of  the  organism  of  syphilis,  and  it  was  succeeded  by  several  more 
in  different  journals.^'  ^*  ^'  ^° 

In  September,  1912,  prompted  by  some  observations  which  he  had  made  with 
spirochaetae  from  guinea-pigs,  E.  H.  Ross  conducted  some  experiments,  with 
material  which  I  had  placed  at  his  disposal.  In  December  he  pubhshed  a  paper-* 
on  some  phases  in  the  development  of  the  Spirochaeta  pallida. 

At  about  the  same  time  my  assistant  Moolgavkar,^^  and  Jennings,-''  working 
with  Ross's  jelly  method,  confirmed  his  observations. 

Some  discussion  as  to  priority  in  discovery  then  arose.  This  subject  need  not 
be  revived  here.  The  whole  matter  is  summed  iip  in  The  Medical  Press  and  Circular,-^ 
to  which  I  would  refer  all  inquirers. 

Although  both  Ross  and  myself  have  described  life-cycles,  there  appear  to  be 


b  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

some  wide  differences  in  the  descriptions  of  the  various  phases.  This  is  doubtless 
due  to  the  fact,  that  Ross  has  not  observed  the  phases  which  he  has  described, 
in  the  living  state ;  and  that  he  has  altogether  neglected  to  examine  the  fixed 
tissue. 

Up  till  the  present,  two  observers — Peyri  Rocamora*i  and  Klausner*^ — have 
repeated  some  of  my  work,  and  both  have  substantiated  my  discoveries. 

Reschad^*^  and  Kyrle,  Mucha  and  Ketron,*^  working  in  Finger's  laboratory, 
repeated  Ross's  work,  using  his  jelly  method,  and  found  that  the  bodies  which  Ross 
had  described  could  also  be  found  in  non-syphilitic  material. 

Roddy*^  worked  at  the  same  subject  in  America,  and  his  results  confirm  those 
of  the  last-mentioned  observers. 

I  have  had  occasion  to  use  the  jelly  method,  which,  as  Herxheimer  and  Reinke'^ 
rightly  point  out,  is  a  modification  of  Carrel's  method.  I  have  not  found  this  method 
very  successful.  The  cells  are  distorted,  they  stain  unevenly,  and  are  soon  killed, 
so  that  impregnation  cannot  be  studied  by  this  means.  I  have  employed  the  borax 
methylene  blue  method,  by  which  the  organism  is  stained  aUve.  By  using  this 
method  the  act  of  impregnation  may  be  witnessed.  To  have  seen  impregnation  is 
important,  since  thereby  the  female  cell  can  be  definitely  ascertained,  and  a  clue  is 
gained  as  to  the  relative  position  of  the  other  phases  in  the  life-cycle.  This  life- 
cycle  is  fuUy  described  in  the  next  chapter. 

1  Lustgarten  (1884),  "  Wien  med.  Woch,"  xxxiv,  1389. 

~  Alvarez  et  Favel  (1885),  "  Arch,  de  physiol.  norm,  et  path.,"  iii,  303. 

3  Klemperer  (1885),  "  Deutsoh.  med.  Woch,"    xi,  809. 

*  van   Niessen  (1908),    "  Der  Syphihsbacillus ;    seine  Geschichte,  Literatur,  Kiiltur,  etc." 

(Leipzig.) 
5  Doehle  (1905),  "Med.  Klinik,"  i.  590. 
«  Clarke  (1907),  '■  Lancet,"  i,  91. 
'  SohuUer  (1905),  "  Deutsche  Arzteztg." 
«  SchuUer  (1905),  "  Berl.  Win.  Woch.,"  xlii,  1275. 
"  Metscliiiikoft'  et  Rous,  Etudes  experinientales  sur  la  Syphilis.    "  Aiui.  de  I'fnst.  Past.," 

1903-1907. 
i»  Metsehnikof=f  etRoux(1905),  "Bull,  de  I'Acad.  de  Med.,"  liii,  468,  et  "  Le  Bull.  MM.," 

441. 
'1  KJinginiiller  u.  Baermann  (1904),  "  Deutsch.  med.  Woch,"  xxi,  766. 
'2  Siegel  (1906),  "  Miinch.  med.  Wocli.,"  liii,  63. 
"  Siegel  (1906),  "  Centralblatt  f.  Bakt,"  xlii,  128,  225,  321. 

■*  Schaudinn  u.  HofEmaim  (1905),  "  Arb.  a.  d.  Kais.  C4esundheitsamte,"  xxii,  527 
•5  Meirowsky  (1914),  "  Dermat.  Woch.,"  Iviii,  225. 
'«  de  Korte  (1906),  "  Practitioner,"  Ixxvi,  786. 
■'  DobeU  (1912),  "  Arcli.  f.  Protistenkunde,"  xxvi,  117. 
■»  V.  Prowazek  (1907),  "Arb.  a.  d.  Kai.s.  Gesundheitsamte,"  xxvi,  23. 


THE   HISTORY   OF   THE   ORGANISM.  7 

'"  Kryzsztalowicz  u.  Siedlecki  (]90o),  "  M.  f.  prakt.  Derm."  xli,  231.  ^ 

'0  Kryzsztalowicz  u.  Siedlecki  (1900),  "  M.  f.  jirakt.  Derm.,"  xliii,  1.  V 

-'  Balfour  (1911),  "  Fourth  Report,  Wellcome  Res.  Lab.,"  Khartoum,  7(5. 

"  Fry  (1912),  "  Proc.  Roy.  Soc,"  Ixxxiv  (Ser.  B.),  79. 

=3  Raiiken  (1912),  "  Brit.  Med.  .Journ.,"  ii.  408. 

"  Henry  (1914),  "  Brit.  Med.  Joum.,"  ii,  1G.'54. 

"  Ross  (1912),  "  Brit.  Med.  Journ.,"  ii,  16,51. 

-'  Moolgavkar  (1912),  -  Brit.  Med.  Journ.,"  ii,  16.5.5. 

='  Jennings  (1912),  "  Brit.  Med.  Journ.,"  ii,  1655. 

2s  McDonagh  (1912),  "  Lancet,"  ii,  1011. 

=9  Editorial  (1913),  "  ]\Ied.  Press  and  Circ,"  ii,  660. 

'"  Reschad  (1913),  "  Arch.  f.  Derm.  u.  Syph.,"  cxviii,  578. 

31  Kyrle  (1914),  "  Arch.  f.  Derm.  u.  Sj^ph.,"  cxis,  213. 

^-  Herxheimer  u.  Reinke(1912),  "  Lubarsch  u.  OstertagErgeb.  d.  Path.  u.  Anat.,"  Jahrg.  16, 

Abt.  II,  45. 
''^  Hoffmann  (1912),  "  Handb.  d.  Geschlechtskranldieiten,"  ii,  784. 
'^  Herxheimer  (1905),  "  Munch,  med.  Woch.,"  lii,  1861. 
^^  Lipschiitz  (1914),  "  Archiv.  f.  Derm.  u.  Syph.,"  cxix,  213. 
3"  Kreibich  (1914),  "  Archiv.  f.  Derm.  u.  Syph.,"  cxix,  213. 
3'  McDonagh  (1913),  '"  Proc.  Roy.  Soc.  Med."  (Path.  Sec),  vi,  8.5. 
'8  McDonagh  (1913),  "  Dermat.  Wocb.,"  Ivi,  413. 
39  McDonagh  (1914),  "Dermat.  Woch.,"  Iviii,  4.5. 
"  McDonagh  (1914),  "  Arcliiv.  f.  Derm.  u.  Syph.,"  cxix.  20.5. 
•"  Peyri  Rocamora  (1913),  "  Revista  de  Med.  Cir.  y  EspeciaUdades,"  vii,  1. 
*'  Klausner  (1914),  "  Archiv.  f.  Derm.  u.  Syph.,"  cxix,  214. 
"  Roddy  (1914),  "New  York  Med.  Jnurn.,"  xcix.  424. 


CHAPTER   IT. 

THE  LIFE-CYCLE   OF  THE   ORGANISM  OF  SYPHILIS. 
{LEVCOC YTOZOON  S YPHILIDIS.) 

The  life-cycle  commences  with  a  spore,  or,  as  it  is  generally  called,  a  sporozoite. 
The  sporozoite,  when  examined  in  vivo,  remains  for  some  time  unstained.  Later 
it  stains  very  deeply,  but  its  motility  is  not  thereby  impaired.  It  is  seen  in  two 
forms — (a)  circular,  (6)  renal-shaped — -its  size  is  about  1'5  microns  in  diameter,  and 
it  is  actively  motile.  Besides  being  found  in  the  scrapings  from  syphilitic  lesions, 
it  may  be  found  in  the  blood  withdrawn  from  the  healthy  skin  surrounding  a 
chancre,  and  also  in  the  general  blood-stream,  during  the  stage  of  general  infection. 
The  sporozoite  then  becomes  intracellular.  On  two  occasions,  I  have  seen  it  in  a 
small  mononuclear  leucocyte  :  it  remained  actively  motile  while  within,  and  it 
ultimately  left  the  cell.  It  chooses  a  connective-tissue  cell  or  an  endothelial  cell  as 
its  host,  and,  when  inside,  it  undergoes  important  changes,  which  can  best  be 
described  under  two  headings  : — 

(1)  The  sporozoite  steadily  increases  in  size,  and,  by  a  process  of  budding,  gives 
rise  to  several  bodies,  which  later  become  differentiated  into  male  and  female  elements. 
By  this  time,  the  cell  is  a  sac,  as  all  the  reserve  material  has  been  used  nj)  by  the 
merozoites  ;  the  niicleus  still  remains,  although  degenerated,  but  finally  it  dis- 
appears, when  the  sac  gives  way  and  frees  the  male  and  female  merozoites.  Not 
all  the  bodies  formed  in  this  way  are  sexually  differentiated  ;  there  are  others  which 
become  free  with  the  sexual  merozoites,  and  are  able,  no  doubt,  to  start  the  cycle 
again,  by  seeking  fresh  connective-tissue  cells  or  endothehal  cells. 

(2)  The  sporozoite  increases  in  size,  but  not  to  the  dimensions  met  with  in  the 
previous  case.  Having  reached  a  certain  size,  it  divides  into  two,  and  again  into 
four.  These  four  masses,  by  a  process  of  further  subdivision,  form  a  ring,  and 
migrate  to  the  periphery  of  the  body,  when  a  picture  is  given  as  if  the  ring  had  stones 
mounted  in  it,  the  whole  way  round.  By  this  time,  the  host  cell  is  almost  completely 
degenerated,  and  one  might  imagine  that  the  parasite  had  become  extracellular, 
but  it  does  so  only  when  the  host  cell  is  no  more.     In  the  centre,  and  around  the 


SCHEMATIC   EEPEESENTATION   OF  THE   VARIOUS   PHASES   OF 
LBVCiK 'YTO'/JXIX  S milL WIS. 


TlIK 


3(;rp)— --(.150^--. 


ASEXUAL 
STAGE 


27     ^      O 


0-*  28^ 


■e-'-b- 


..®;. 


-<-SL....-X|' 


J 

-5. 

G- 

-13. 

1- 

-13. 

U- 

-1:1. 

U. 

1.x 

Iti, 

17. 

18, 

19. 

•-'0 

-ih. 

23. 

24. 

2.=). 

26 

-29. 

i<S 

27. 

2S 

31). 

31 

-3(1. 

31. 

32. 

33. 

o7 

-39. 

Development  of  spore  iuside  a  cell  up  to  the  stage  ia  which  sexual  morozoites  (5)  are  formerl. 

Asexual  developnieut  of  the  spore. 

Represeut  what  is  called  "Schizogony,"  a  term  which  simply  means  reproduction  by  fission. 

Intracellular  development  of  the  male  body. 

IMale  gametocyte. 

Male  gametocyte  in  a  large  mononuclear  leucocyte. 

Development  of  male  gametocyte  into  spirochaetal  coil. 

Development  of  the  Sjurochaefa  pallida. 

Extracellular  development  of  the  male  gametocyte. 

The  coccal-liko  chain. 

The  diplococcal-like  body. 

Tile  refringeus-like  form  of  the  immature  ^pirovhaei a  pallida. 

Development  of  the  female  body. 

Ft-male  gametocytes  with  blepharoplasts. 

Female  gametocyte  witliout  blepharoplasts. 

Female  gamete. 

Fertilisation  of  female  gamete  by  the  Spirockaefa  pallldft. 

Development  of  the  zygote  and  sporoblasts  into  sporozuites. 

Zygote. 

Binary  fission  of  zygote. 

Sporoblasts. 

Development  of  an  escaped  sporoblast  into  sporozoites,  i.e.  spores. 


Plate  2. 


Facing  p.  8. 


THE   LIFE-CYCLE    OF   THE    LEUCOCYTOZOON    SYl'HILIDIS.  5) 

ring,  other  deeply  stained  bodies  appear,  until  a  picture  of  a  perfect  spore  cyst  is 
given.  This  is  doubtless  the  true  asexual  stage,  and  the  two  stages  just  described 
represent  the  schizogony. 

The  asexual  differs  from  the  sexual  spore  cyst  in  two  points  ;  first,  the  asexual 
spore  cyst  frequently  has  one  or  two  daughter  spore  cysts  attached  to  its  periphery  ; 
secondly,  the  spores  in  the  asexual  spore  cyst  are  smaller  than  those  in  the  sexual 
body.  When  the  asexual  stage  is  the  only  stage  that  develops  (vide  Chapter  III), 
these  differences  are  not  to  be  met  with.  The  parasitic  bodies  are  larger  and 
altogether  better  developed. 

Both  the  male  and  female  gametocytes  are  motile,  but  not  flagellated.  The 
male  consists  of  three  nuclear  bodies  ;  while  the  female  contains  a  nucleus  at  her 
upper  end,  and  one  or  two  very  actively  motile  blepharoplasts  at  her  lower  end. 
AVhen  the  female  has  reached  the  size  of  a  red  blood  corpuscle,  she  loses  her  blepharo- 
pla.sts  and  becomes  stationary.  Before  fertilisation,  the  nucleus  of  the  female  gamete 
moves  from  the  upper  pole,  takes  a  central  position,  and  fills  up  practically  the  whole 
cell. 

The  male  gametocyte  may  develop  intracellularly  or  extracellularly.  If  the 
former,  it  enters  a  large  mononuclear  leiicocyte,  wherein  the  three  nuclear  bodies 
increase  in  size,  develop  into  a  coil,  and  from  each  nuclear  body  a  immber  of  spiro- 
chaetae  arise,  like  the  spokes  of  a  wheel  from  its  axle.  The  spirochaetae  break  loose, 
and  each  can  then  be  recognised  as  a  true  Spirochaeta  pallida.  In  the  extracellular 
development,  each  nuclear  body  divides  and  subdivides,  so  that  a  rosette-like  appear- 
ance is  formed.  Several  borlies  may  break  away  en  masse,  in  the  shape  of  a  chain, 
which  ultimately  breaks  up  into  distinct  coccus-like  forms  ;  or  discrete  coccus-like 
forms  may  at  first  break  away.  Each  coccus-like  body  contains  two  rods,  which 
give  it  the  appearance  of  a  diplococcus,  and  these  rods  develop  into  thick  and  un- 
evenly coiled  spirochaetae,  which  eventually  become  typical  Spirocliaetae  pallidae. 

The  intracellular  development  has  been  found  in  every  syphilitic  lesion  so  far 
examined  by  me,  while  the  extracellular  development  has  been  found  to  occur  in 
chancres,  condylomata,  a  brain  from  a  case  of  degenerative  encephalitis,  and  in 
some  congenital  syphilitic  lesions. 

The  immature  spirochaeta,  which  is  first  formed  in  this  extracellular  route, 
resembles  the  refrijigens  type  ;  therefore  it  is  very  probable  that  a  spirochaeta,  in 
two  stages  of  its  development,  is  indistinguishable  from  the  Spirochaeta  refringens 
and  the  Spirochaeta  pallida. 

Fertilisation,  again,  does  not  always  appear  to  take  place  in  the  same  stereotyped 
manner  ;  as,  in  some  cases,  the  spirochaeta  appears  to  enter  the  female  nucleus, 
wherein  it  becomes  lost  ;   or,  in  other  cases,  it  seems  to  become  connected  with  the 


10  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

female  nucleus  by  a  skein.  lu  both  cases,  the  nucleus,  which  contains  both  male 
and  female  elements,  migrates  again  to  the  upper  pole  ;  such  a  cell  is  a  zygote. 

In  the  nine  instances  in  which  fertilisation  has  been  studied  by  me,  only  one 
spirochaeta  has  been  observed  to  enter  the  female,  and  it  takes  about  an  hour  to 
become  entirely  lost  to  view.  While  entering,  the  whole  cell  is  in  active  motion, 
but  once  the  spirochaeta  has  entered,  the  cell  comes  to  a  sudden  standstill,  and 
appears  to  become  covered  with  a  mantle. 

A  few  minutes  after  impregnation,  a  polar  body  is  expelled  with  considerable 
force  from  the  cell,  and  again  another,  after  an  interval  of  a  minute  or  two.  During 
the  extrusion  of  the  polar  bodies,  the  cell  is  very  actively  motile,  but  it  becomes 
stationary,  immediately  after  the  second  has  been  ejected. 

The  nucleus  of  the  zygote  divides  and  subdivides  into  sporoblasts  ;  the  sporo- 
blasts  may  further  divide  and  subdivide  in  situ,  to  form  sporozoites  ;  or,  a  sporoblast 
may  escape  and  form  sporozoites  independently. 

From  the  above  description  of  the  hfe  history  of  the  organism  of  syphilis,  I 
think  I  am  justified  in  assigning  it  to  the  order  Sporozoa,  and  to  the  sub-class  Telo- 
sporidia,  since  the  spores  are  formed  at  the  end  of  a  cycle.  The  order  is  doubtless 
the  Coccidiidea  and  the  species  which  most  befits  it  is  the  Leucocytozoon  ;  hence 
a  good  name  for  the  syphilitic  parasite  would  be  Leucocytozoon  syphilidis,  or  simply 
Coccidium  syphilid  is. 

Glossary. 

TROPHOZOITE  means  a  protozoal  body  parasitic  on,  and  therefore  nurtured  by,  one  of  the 

cells  of  the  host. 
MEROZOITE  means  division  of  a  protozoal  bo^dy. 
GAMETOCYTE  means  a  cell  which  gives  rise  to  a  reproductive  cell. 
BLEPHAROPLASTS  are  the  same  as  the  nucleoli  of  nuclei. 
GAMETE  means  the  adult  sexual  cell. 

ZYGOTE  means  the  product  of  fusion  between  two  sexual  bodies. 
SPOROBLAST  means  a  body  that  is  going  to  give  rise  to  spores. 
SPOROZOITE  means  an  animal  spore,  in  contradistinction  to  a  vegetable  spore. 

WORKS  CONSULTED. 

Ray  Lankester  (1903),  "  A  Treatise  on  Zoology."     (Part  L)     A.  and  C.  Black.     London. 
Schaudinn  (1911),  "  Arbeiten  Fritz  Schaudinns."     L.  Voss.     Leipzig. 

Kolle  u.  V.  Wassermann  (1913),  "  Handbuch  der  Pathog.  Mikroorganismen."     Z^\•cite  Aufl. 
vii.     G.  Fischer.     Jena. 


PHOTOGRAJPHS. 
X  1500. 


^ 


^* 


'A 


St^ 


\ 


^m.^ 


Ti"u]tlHi/.uitL'  ill  ciniiirrtivL'-tis^JUi.'  cell  ci.niiiiR'uciiii;-  tu 
Imd  to  funn  tsuxual  luerozoites. 


I)uVL'lu|.itii;  ti'iipln..z"it.c  ill  cuiiiirctive 
ti.ssuo  cl'II. 


FuvtlKT  .stage  of  in-ocefliiii;-  pliutny-mpli. 


Sexiuil  luerozoitfs  in  protoplasm  of  couuectivo- 
tissue  cell.  Upper  body  is  a  female  luerozuitt.', 
lower  body  consists  of  immature  male  merozoites. 


Plate  3. 


I'lfitcs   ;J-I1,  f'lriiKj  j>ii,jc   10, 


^1  *?  V 


Troplio/Aiitu  iu  couiiectivu-t  issue  cull. 


liiiiary  lission  (if  tiYtjtlKizuitc  in  (.'niiiiL'otivc-tissiU'  cell. 


First   siiliilivisi(»n  of 
iisuxual  sjior 


ti'ophozuiU' tnwiirds  funimtimi  u[ 
0  cyst  ill  (Mirlntlu'lial  cell. 


Fiiiilicr    stage   of    pvoceiling'    plu 
coiiimonoinp;  (Ict^enoration  of 


itog^rapli.      Nnte 
host's  cell. 


Plate  4. 


Asexiuil    spi.iro  cyst.     Note   contpK^tc    degoiiuratioii  o[ 
the  host's  cell. 


Asexual  spore   cyst   ■\\'ith  daugliter   spore    cyst. 
Endothelial  cell  almost  degenerated. 


Asexual  spore  cyst  witli  daughter  spore  cysts.     Host's 
cell  lias  quite  degcuerated. 


Male  g.nmctocyte  after  it  has  left  counective-tissue 
cell. 


Plate  .'i. 


I 

1 


13.  H. 

M:ili-  i;ami-toovtc  iiisitli'  a  hivge  iiuniiiinii-li-iir  li-ii.ocyte.  Malo  gametocyte  with  tbref  uucli-ar  Ixidies.     Nucleus 

of  mouonuclear  shows,  but  it  is  out  of  focus. 


#*  ^ 


if 


% 


'-A 


l.V  III- 

Devolojiuieut  of  the  thi-co  uuch-ar  bodies  of  tlie  mah-  Further  developiueiit  of  the  three   uuch'ar  bodies 

gametocyte  iu  the  protoplasm  of  a  large  uiouuiiuelear  towards  formatiou  of  spirocbtetal  coil.     Nucleus 

leucocyte.  of  uiououuclear  is  tii  riglit  and  out  of  foeiis. 


Pl..\TE    G. 


/ 


Jl     '^ 


4 


f 


Spii-oclio?tiil  coil. 


IS. 
Kxtvai't'Iliilar  .levi'Iopniriit  nt  male'  gainc'tooytu. 


/ 


Fm-t.liiT  stage  of  iiviM-i'ilini;  iiliofogniijli. 


Further  stagi.'  of  procnling  pliotograpli. 


Plate 


21.  2-.'. 

Feniali'  ganu'tocyti'  "with  (.nn-  lilcplinroiilast.  Fi'iiiale  ^■aiui'tm^yto. 


23.  24. 

Female  gamete.  rai-tlii'inigciictii:  (lovelopmeiit  vi  fi'iiialr  gamete. 


Plate  8. 


I 


^r--J^      e  •  1 


■J.'l.  ■ill. 

Fuinale  yaiiicti;  after  iiiipvfjfiiatiou.      Note   skuiu  Zyguto. 

bctWL'oii  iiialo  auf-1  fomalo  cletiients. 


jp  ••       «?  < 


r.inary  Hssiou  of  zygote.  Stage  after  biliary  ti,ssi<.ii  of  zygote. 


4 


■20. 
S}n'rulilnst  fnnnatiitn  nf  zyg'utr. 


Fni'tlirr  cli'vcliipiiic'iit  (if  siHii-ol)I:isti 


^«< 


(f5 


•% 


«! 


<s 


IM^A 


;;i. 


Si'xual  spore  cyst. 


Suxiial  spore  cyst  with  an  escaping  spurulilast. 


Plate  10. 


«: 


# 


8|»urublat>t  wldcli  "wiJl  funii  ^■p^'l■(lzuit^.s. 


34, 

Escaped  sporoblast  with  a  spnruzuite. 


•n 


% 


•  * 


Biuary  fissiou  of  sporoblast. 


Sporozoites  developed  from  a  sporolilast. 


Plate  U. 


I 


Plate  12. 


1. 


Section  of  the  cerebral  cortex  from  a  case  of  degenerative  encephalitis, 
stained  with  pyronin  and  methyl  green. 

A.  Developing  trophozoite  in  a  connective-tissue  cell. 

B.  Aminoplasma  cell. 

C.  Nucleolus  from  a  degenerated  nerve  cell. 


Section  of    a  late  recurrent  cutaneous    pnpular  sj-philide,  stained   witli 
pyronin  and  methyl  green. 

A.  Male  gametocyte. 

B.  Male  gametocyte  in  a  large  mononuclear  leucocyte. 
C.D.E.  Intracellular  and  extracellular  spirochaetal  coils. 


®) 


<g- 


Follows  Plain  11. 


Plate  12. 


.21  stajT 
.1 

.noii^  [yrfloHi  bxif,  ninoiyq  rfiiv/  baniista 

.llao  aueail-aviJoonnoa  «  ni  oiiosoriqoil  gniqoIavsQ  .A 

Also  tiraFtslqonicaA  .3. 
.lleo  f)Vi9n  I)Oi)OT9nojJof)  Ji  nioi^  «t;lo9loi/'H  .0 

.S  ' 

(l.tiv/   hqfiip.ia  .obillriq-^e  ijiluqjiq   Ri/oiniiJtio  inanr/ooT  oijsl  «    lo  noiioot^ 

.no9in  Ii^rilom  bnc  ninoivq 

.9li{oolomB8  gfjsM  .A 

.9iyoootnl  ijiolorrnonom  9s7cl  c  ni  oiyooi'oiui^  9kM  .fl 

.s(ioo  lsi'ir,iho-iii[?.  iKlurfnmtzo  brui  uJi/lbrunlnl   ..T.fT.O 


.tt  MnSI  wioVW* 


)    @          *    -1                 \ 

J  ^            / 

ir      s)                           gj        / 
©    .^        IS,             ^'^-^- ^c 

Plate  12. 


Plate  13.  • 

1. 

Section  of  a  chancre,  stained  with  pyroiiin  and  methyl  green.  The  tissue 
was  hardened  in  acetic  acid  alcohol,  in  order  to  enable  the  methyl  green 
to  reach  the  parasitic  nuclein. 

A.  Female  gamete  just  after  fertilisation  in  process  of  expelling  polar 

bodies. 

B.  An  expelled  polar  body. 

C.  The  second  polar  body  about  to  be  expelled. 


Section  through  the  base  of  a  foreskin,  upon  the  tip  of  which  was  situated 
a  chancre,  stained  with  pyronin  and  methyl  green.  The  figure  below  and 
to  the  right  is  the  naked  eye  appearance  of  the  section,  and  the  small  black 
ring  represents  the  area  from  which  the  painting  was  made. 

A.  A  spore  cyst  in  a  vessel  wall.     This  figure  shows  how  the  parasites 
spread  from  the  initial  lesion. 


Plate  13 

Follows  Plate  12. 


.fit  aTAj'l 

.1 

ousaii  oilT     .noyig  IyiWouj  ban  iiiiioiX"!  'l>ti"  bunw;ta  ,oioiu;iio  j>  lo  noiioyfci 
naoig  lijiliam  odi  ofdiins  oi  lobio  ni  Jorioolfi  biofi  oM9db  ni  bsnabieri  w// 

iailo<i  gnilloqz'j  lo  aaooo'iq  iii  noiJjJisilitiol  ■ioJIb  iaoi  aioaiBg  oLeiria'tt  .A 

.gaibod 
.^bocf  ijjlcHj  l)!jUof(xu  iiA  .a 
.ballotjxa  ad  oJ  vtuodjj  -^jbod  icloq  baooo?.  oriT  .0 


boJjii/iig  ajB7/  daidv/  lo  qii  f)((i  noqi;  .ni/lgoiol  «  lo  ORjsd  eili  riguOTrlJ  noiioaB 
bnfi  wolod  9iugft  ailT     .nao-ig  ly_di9i<\  baa  ninoivq  dibii  ben'min  .aiaaeiio  e 
AoKki  IIbhip.  ad'l  bae  ,noiloyg  axli  lo  aonjiiij'jqqji  a^^y  bodisn  9x{J  t.i  ddgh  adi  oJ 
.abjsm  auvf  gniiniBq  adt  doidw  nioil  eaifi  adJ  Blnaeaiqai  gnii 

EotieBiJsq  ad^  v/od  Bworis  am§3  airiT     .Hew  [a8«3V  «  ni  jk^o  aioqa  A  .A 

.iioiisal  Imiini  aili  iiicnl  bcaiqs 


.2f  »hin  wioHo'^l 


Plate  13. 


CHAPTER  III. 

ABERRANT  DEVELOPMENT   OF  THE  LIFE-CYCLE. 
AND   COCCIDIOSIS   AVENEREA. 

Every  syphilologist  must  have  been  struck  by  the  extraordinary  variations 
to  be  met  with  in  priniary  sores.  One  notes  the  variation  in  the  time  of  incubation, 
the  difierence  in  the  rate  at  which  the  sore  disappears,  irrespective  of  treatment, 
and  the  protean  nature  of  the  future  course  of  the  disease. 

The  variations  to  be  met  with  in  the  rashes  can  be  explained  on  anatomical 
grounds,  as  will  be  seen  later.  The  variations  witnessed  in  the  initial  lesions  cannot 
be  so  explained. 

The  amount  of  virus  which  enters  the  host,  when  he  becomes  infected,  and  the 
degree  of  resistance  which  the  host  offers,  will  not  suffice  to  explain  why  chancres 
exhibit  such  diverse  clinical  features,  since  the  same  factors  come  into  play  in  soft 
sore  infections,  but  the  chnical  varieties  of  a  soft  sore  are  not  numerous.  Even  the 
Ulcus  molh  serpiginosum,  when  examined  closely,  has  all  the  clinical  features  of 
a  soft  sore.  It  is  mainly  the  course  run  by  the  two  conditions,  which  serves  to 
distinguish  this  chronic  ulcer  from  a  soft  sore.  This  variation  is  due  to  a  change 
in  the  habits  of  the  organism,^  {vide  Chapter  XXXI).  In  the  plain  Ulcus  molle, 
Ducrey's  bacillus  is  an  extracellular  organism.  In  the  complication,  Ulcus  molle 
serpiginosum,  Ducrey's  bacillus  is  mainly  an  intracellular  organism. 

This  shght  clinical  difference  in  the  soft  sore  infection  is  due  to  a  difference  in 
the  mode  of  living  of  the  same  organism.  Is  it  not  therefore  more  than  likely  that 
the  extreme  clinical  variations,  to  be  met  with  in  the  syphiUtic  infection,  are  due 
to  differences  in  the  life  history  of  the  causative  organism  ? 

The  clinical  observations  mentioned  above,  all  tend  to  disprove  the  theory 
that  the  Spirochaeta  pallida  is  the  only  phase  in  the  life  history  of  the  sj^philitic 
parasite.  Since  the  adult  Spirochaeta  pallida  is  never  seen  intracellularly  situated, 
some  other  phases  must  be  present,  and  in  the  one  case  some,  and  in  the  other  case 
others  predominate. 

The  chnical  variations  of  the  primary  sore  have  a  wider  significance  than  that 


12  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF    SYPHILIS. 

of  merely  suggesting  that  phases  other  than  the  spirochaeta  exist.     They  suggest 
that  the  life-cycle  itself  may  run  an  aberrant  course. 

It  is  a  well-known  fact  in  protozoology,  that  the  female  cells  may  develop 
without  being  fertilised,  and  to  such  a  phenomenon  the  term  Parthenogenesis  has 
been  given. 

As  a  result  of  several  in  vivo  examinations,  which  I  have  made  of  syphilitic 
material,  I  believe  that  the  female  gametes  of  the  Leucocytozoon  syjihiUdis  can 
develop  by  parthenogenesis  (Plate  8  (24) ),  but  more  important  still,  I  believe 
that  in  some  cases,  only  the  asexual  stage  develops. 

The  following  case  is  what  I  take  to  be  the  clinical  course  of  a  case  of  syphilis 
in  which  the  organism  develops  asexually  only. 

Case  1. — The  patient,  a  man,  aged  41  years,  came  up  for  consultation  in  October, 
1913,  complaining  of  a  rash  on  the  penis.  Nineteen  years  ago  the  patient  had 
a  sore  on  the  penis.  The  sore  appeared  some  weeks  after  connection,  remained 
single,  was  about  the  size  of  a  sixpenny  piece,  the  ulceration  was  superficial,  the  sore 
did  not  increase  in  dimensions,  there  was  little  or  no  discharge  from  it,  and  it  took 
some  months  to  heal.  A  medical  man  was  consulted  at  the  time,  and  he  ordered 
local  treatment  only,  and,  as  far  as  can  be  ascertained,  no  diagnosis  was  made. 
The  sore  was  not  followed  by  sweUings  in  the  groin,  and  no  other  symptoms  appeared, 
imtil  early  in  1913.  In  the  meantime,  the  patient  had  always  enjoyed  the  best  of 
health,  except  for  occasional  attacks  of  dyspepsia,  which  still  troubled  him. 

The  patient  had  spent  some  time  in  West  Africa,  but  the  sore  appeared  in 
England,  before  he  had  visited  the  tropics.  Patient  was  married,  but  had  had  no 
cliildren,  and  his  wife  had  never  been  pregnant. 

The  rash  for  which  the  patient  sought  advice,  was  a  ringed  eruption  in  the 
circumference  of  the  original  sore,  and  a  smaller  similar  lesion  which  appeared  later, 
below,  and  somewhat  to  the  outer  side,  but  quite  separate  from  the  first  lesion. 
The  original  sore  had  left  a  scar,  around  which  was  a  raised  ring  made  up  of  almost 
discrete  papules.  Some  of  the  papules  appeared  to  have  a  little  pus  in  them,  but 
no  matter  came  away  upon  puncturing  them.  Other  papiiles  were  covered  by  a 
small  hard  crust,  which,  on  removal,  disclosed  a  scar  but  no  ulceration.  The  lesion 
below  was  similar,  and  with  neither  was  there  any  surrounding  inflammation. 

I  beheved  that  the  lesions  were  syphiUtic,  and  that  the  original  sore  was  a 
primary  chancre.  The  patient  had  never  shown  any  other  symptoms  of  syphihs  ; 
he  had  never  taken  any  treatment,  and,  on  a  thorough  examination,  no  other  signs 
of  syphilis  were  revealed. 

The  Wassermann  reaction  was  slightly  positive  (  +  ).  The  patient  then  received 
four  weekly  intravenous  injections  of  neo-salvarsan,  some  intramuscular  injections 


Aberrant  Development  of  the  Leucocytozoox  Svpiiilidis, 

A.  Trojiliozoite  iu  couuective-tissue  cell.     Note  degeuevatecl  nucli*us  of 

counective-tissue  cell  above  ami  to  the  left  of  the  parasite 

B,  C,  D,  F,  H.     Developiug  sporoblasts, 

E.     Sporozoite  below  aucl  divuliujj:  sporoblast  abovi.'  the  Hue. 
G.     Spore  cyst. 

Iu  H  uote  besides  the  four  big  bodies  a  tiuy  bodj'  above  aud  to  the 
left.  Iu  my  opiuion  it  serves  the  fuuction  of  a  bleidiaroplast  or  uucleolus, 
heuce  its  presence  in  asexually  developing  cells,  since  it  is  not  found  iu 
zygotes. 


Plate  14. 


Fncing  p.  I'Z. 


ABERRANT   DEVELOPMENT   OF   THE    LEUCOCYTOZOON    SYPHILIDIS.  13 

of  mercury,  and  potassium  iodide  internally ;  local  appKcations  of  ung.  liydi'arg. 
and  ung.  iodex  were  also  prescribed.  In  spite  of  all  this  treatment,  the  lesions  are 
very  much  the  same  to-day  as  when  they  were  first  seen,  and  the  Wassermaun 
reaction  remains  indefinite  ( — h). 

Clinically,  the  condition  was  unlike  anything  else  except  syphilis,  but  as  it  was 
odd  that  anti-syphilitic  treatment  had  proved  unavailing,  a  portion  of  the  granuloma 
was  removed  for  microscopic  examination.  Several  sections  were  cut  and  stained 
(Plate  14).  In  all,  the  bulk  of  the  cellular  infiltration  was  limited  to  the  corium, 
and  any  inflammation  in  the  subdermic  tissue  was  in  and  around  the  A\'alLs  of  the 
blood  vessels.  The  cellalar  infiltration  was  mainly  composed  of  lymphocytes  and 
plasma  cells.  In  some  sections,  the  cellular  infiltration  was  grouped  into  small  areas, 
which  were  surrounded  by  connective  tissue.  In  some  areas,  several  giant  cells 
were  to  be  seen,  which  might  have  suggested  a  tuberculous  lesion,  but  in  other 
areas  necrosis  had  taken  place,  leaving  behind  an  amorphous  mass,  which  stained 
badly,  suggestive  of  either  caseation,  or,  more  probably,  a  gumma.  Any  vessels 
visible  showed  marked  cellular  infiltration,  both  in  their  walls  and  in  the  peri- 
vascular tissue.  In  other  sections,  the  cellular  infiltration  was  diffuse,  there  were 
more  plasma  cells,  no  giant  cells  were  visible,  and  the  various  phases  of  the  Leucocyto- 
zooH  sypliilidis  were  clearly  discernible.  The  pecuhar  features  about  the  phases  were, 
the  entire  absence  of  any  male  and  female  bodies,  and  the  presence  only  of  intracellular 
and  extracellular  developing  spores. 

Against  the  view  that  the  gametal  forms  had  been  destroyed  by  the  treatment, 
was  the  fact  that  the  lesions  had  remained  unaltered  in  spite  of  it.  The  suggestion 
arose,  that  the  case  was  an  aberrant  form  of  syphihs,  in  which  only  the  spores  had 
been  able  to  develop  asexually.  In  favour  of  the  suggestion  were  the  following 
points  :— 

(«)  The  chronicity  of  the  lesions  ;  (6)  the  extreme  locahsation,  with  no 
ascertainable  evidence  of  any  generalised  infection  ;  (c)  the  weak 
positive  Wassermauu  reaction  ;  {d)  the  insensibihty  of  the  lesions  to 
treatment. 

CUnically,  the  case  was  of  extreme  interest,  and  so  were  the  histological  ap- 
pearances. Unless  one  had  been  able  to  find  the  syphilitic  parasite,  it  would  have 
been  impossible  to  diagnose  the  condition  from  any  other  form  of  gi'anuloma. 

Another  point  of  interest  in  the  case  was,  that  the  wound  resulting  from  the 
biopsy  healed  by  first  intention,  while  the  site  of  the  original  sore  broke,  down,  and 
ulcerated  again.  The  ulceration  healed  in  three  weeks.  The  tendency  for  sites  of 
primary  sores  to  break  down  years  afterwards,  as  a  result  of  trauma,  is  very 
characteristic. 


14  THE   BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

Finally,  it  may  be  stated  that  the  parasitic  bodies  gave  the  same  micro-chemical 
and  physical  tests  as  are  described  in  Chapter  VI. 

To  obtain  further  evidence  upon  what  might  be  considered  an  extremely 
imaginary  conception,  I  examined  several  chancres  for  spirochaetae.  and  I  excised 
those  in  which  I  found  none,  for  further  examination.  I  was  soon  successful  in 
finding  one  sore  which  histologically  resembled  in  detail  the  figure  accompanying 
the  preceding  case. 

The  sore  was  situated  on  the  skin  of  the  penis  ;  round,  perfectly  circumscribed, 
about  1'25  cm.  in  diameter.  There  was  no  surrounding  inflammation,  and  the 
sore  was  an  erosion,  and  not  an  ulcer — the  characters  of  a  true  syphilitic  sore.  Some 
time  later,  an  unevenly  circumscribed  ulcer  appeared,  also  on  the  skin  of  the  penis, 
3 '75  cm.  above  the  primary  sore,  nearer  the  pubis.  This  ulcer  had  evidently  arisen 
from  a  subjacent  lymphangitis.  The  lymphatic  glands  in  the  groin  were  not 
enlarged,  the  patient  never  developed  further  symptoms,  and  the  Wassermann 
reaction  was  never  positive,  not  even  six  months  and  a  year  later,  in  spite  of  the 
fact  that  no  anti-syphilitic  treatment  was  ever  prescribed. 

In  those  cases  in  which  a  man  has  had,  at  different  times,  two,  and  even  three 
chancres,  without  ever  developing  further  syjnptoms,  or  giving  a  positive  Wasser- 
mann reaction,  is  it  not  possible  that  the  organism  developed  aberrantly  ? 

There  is  a  syphilitic  primary  sore  which  sometimes  is  never  followed  by 
further  symptoms,  the  lymphatic  glands  may  not  even  enlarge,  and  the  sore  is 
extremely  resistant  to  treatment.  There  may  be  one  or  more  sores,  and  their 
appearance  is  characteristic.  The  sore  is  sharply  circumscribed,  the  base  is  an 
ulcer,  uneven,  and  usually  yellow,  although  it  is  not  actually  covered  with  pus. 
The  edges  are  raised,  a  little  swollen,  slightly  inflamed,  but  not  undermined.  The 
circumference  is  not  always  perfectly  regular,  as  the  sore  spreads  somewhat,  and 
not  equally  in  all  directions. 

This  kind  of  sore  is  most  frequently  seen  on  the  under  surface  of  the>  prepuce. 

I  have  had  the  opportunity  of  thoroughly  examining  five  such  sores,  four 
were  primary  sores,  and  the  fifth  was  a  chancre  redux.  In  the  case  of  the  chancre 
redux,  the  patient  had  contracted  syphilis  29  years  previously,  and  in  the  mean- 
time had  never  had  a  syphilitic  symptom.  Around  the  chancre  redux  were 
smaller  satellite  sores,  all  of  which  had  the  same  clinical  features. 

Neither  salvarsan  nor  mercury  had  the  slightest  influence  on  these  five 
cases. 

Histologically,  no  spirochaetae  could  be  found,  but  the  asexual  phases  of 
the  leucocytozoon  were  easily  demonstrable  in  section. 

From  the  cases  just  mentioned,  it  would  appear  that  when  only  the  asexual 


ABERRANT  DEVELOPMENT  OF  THE  LEUCOCYTOZOON  SYPHIUDIS.         15 

stage  of  the  Leucocytozoon  syphilidis  develops,  the  course  nui  by  the  disease  is 
a  chronic  one,  and  the  Wassermann  reaction  is  of  no  value  as  a  diagnostic  agent, 
since,  out  of  the  last  five  cases  mentioned,  the  reaction  was  negative  in  four,  and 
was  positive  in  the  chancre  redux  case  only.  The  histological  appearances  of  the 
sections  from  these  cases  resemble  very  closely  those  seen  in  Granuloma  inguinale — 
indeed,  the  parasitic  bodies  are  very  similar  [vide  Plate  42).  The  lesion  of 
Granuloma  inguinale  is  essentially  a  chronic  one  ;  the  Wassermann  reaction  is 
not  positive,  and,  as  a  rule,  the  condition  is  not  improved  by  salvarsan — three 
points  which  tally  exactly  with  the  syphilitic  lesion,  when  only  the  asexual  stage 
of  the  parasite  develops. 

Sequeira*  recently  had  a  very  remarkable  case,  the  microscopic  pictures  of 
which  were  not  at  all  unlike  those  of  the  lesions  under  discussion.  The  patient 
was  a  boy,  aged  7,  thin  and  anaemic.  He  complained  of  a  rash  which 
had  only  recently  developed,  and  which  was  diagnosed  as  Lichen  jjkmus.  Some 
months  later,  the  rash  further  developed,  and  each  lesion  of  it  was  distinctly 
xanthomatous  in  appearance.  About  the  same  time,  Diabetes  insipidus  ensued, 
soon  after  which  the  patient  died. 

Unfortunately,  a  Wassermaim  reaction  was  not  done,  as  Diabetes  insipidus 
in  children  is  very  commonly  a  symptom  of  congenital  syphilis,  and  is  due  to  a 
lesion  in  the  posterior  lobe  of  the  pituitary  body.  Curiously  enough,  the  case 
in  hand  had  a  lesion  in  this  gland.  With  Dr.  Sequeira's  kind  permission,  I  am 
able  to  give  here  the  report  on  the  histology  of  the  sections  which  I  submitted 
to  the  Pathological  Committee  of  the  Dermatological  Section  of  the  Eo}-al  Society 
of  Medicine. 

Epidermis. — The  epidermis  is  thinned  in  some  parts,  but  the  processes  are 
markedly  elongated,  and,  in  between  some  of  the  epithelial  cells,  are  a  few  stray 
leucocytes.  The  basal  la}'er  of  the  epidermis  over  the  cellular  infiltration  of  the 
corium  is  depigmented.  A  similar  picture  is  to  be  seen  in  sections  of  most  syphilitic 
and  tubercular  skin  lesions. 

Corium. — The  cellular  infiltration  reaches  as  far  up  as  the  epidermis.  It  is 
especially  noticeable  in  the  papillae,  and  ^this  arrangement  no  doubt  accounts 
for  the  prolongation  of  the  epidermal  processes  on  either  side.  Laterallj-,  the 
infiltration  is  not  circumscribed,  but  below,  it  does  not  reach  as  far  down  as  the 
sweat  glands.  The  topography  of  the  cellular  infiltration  strongly  suggests  a 
parasitic  infection,  which  has  reached  the  skin  by  way  of  the  blood  stream. 

The  cellular  infiltration  consists  mainly  of  endothelial  cells.  There  are  several 
polymorphonuclear  leucocytes,  fewer  lymphocytes,  and  only  a  few  embryo  lympho- 
cytes and  eosinophile  cells.     I  could  find  no  cells  which  I  took  to  be  plasma  cells. 


16  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TEEATMENT   OF    SYPHILIS. 

The  endothelial  cells  are,  for  the  most  part,  normal,  the  protoplasm  behig 
perhaps  a  little  irregular  and  degenerate.  There  is  no  nuclear  or  nucleolar 
activity.  Most  of  the  endothelial  cells  have  only  one  nucleus,  and  each  micleus 
has  only  one  imcleolus.  Hence,  so  far  as  the  endothelial  cells  are  concerned, 
the  lesion  is  an  inflammatory  one,  and  not  a  new  growth.  Several  of  the 
endothelial  cells  have  coalesced  to  form  giant  cells. 

Some  of  the  endothelial  cells  recpiire  very  special  mention.  The  protoplasm 
is  sacculated.  The  outline  of  the  sack  is  very  distinct,  and  is  attached  to  the 
nucleus  at  its  two  ends.  Between  the  attached  portions,  the  outline  of  the  nucleus 
is  concave.  The  groundwork  of  the  sack  is  unstained.  In  the  sack  one  or  more 
cells  are  to  be  seen,  the  morphology  of  which  varies  in  the  different  cells  examined. 

In  some,  the  cell  is  very  small,  and  appears  to  consist  of  nuclear  material  only  ; 
in  others,  the  nuclear  material  is  much  bigger,  stains  very  darkly,  is  homogeneous, 
and  lies  in  a  mass  of  protoplasm,  which  is  perfectly  circumscribed,  regular,  and 
slightly  refractile.  In  other  endothelial  cells,  instead  of  one  mass  of  nuclear 
material,  there  appear  to  be  four  masses,  and  each  of  the  four  divisions  consists  of 
two  masses  of  nuclear  material,  with  protoplasm  between  each.  In  still  other 
cells,  six  or  more  bodies  are  to  be  seen.  Each  one  is  either  made  up  of  the  two 
nuclear  masses  just  described,  or  these  two  nuclear  masses  have  increased  to  three 
or  four,  as  if  they  had  undergone  division. 

Similar  bodies  in  groups,  and  occasionally  single,  are  to  be  seen  extracellularly 
situated. 

I  have  seen  bodies  siniilar  to  these  in  Granuloma  iropicum.  In  the  case  of 
the  tropical  granuloma,  by  emploj^ing  various  micro- chemical  tests,  I  have  come 
to  the  conclusion  that  they  are  parasitic  bodies,  and  that  they  are  probably  phases 
in  the  asexual  development  of  a  coccidial  protozoon  (vide  Plate  42). 

The  sacculation  of  the  protoplasm  of  the  endothelial  cells,  and  the  very  deep 
staining  of  the  nucleus  of  the  included  bodies  are  very  suggestive  of  parasitism. 

In  the  section  stained  with  haematox3'lin  and  Sudan  III,  fat  is  demonstrable, 
both  outside  and  inside  the  endothelial  cells.  This  is  probabh'  to  be  regarded  as  a 
degeneration  product  of  the  protoplasm  of  the  endothelial  cells.  It  is  likely  that 
xanthoma  is  not  a  disease  sui  generis,  but  merely  granulation  tissue,  composed  of 
endothelial  cells,  in  which  the  protoplasm  has  undergone  fatty  degeneration. 
When  an  enormous  number  of  endothelial  cells  is  formed,  as  in  this  specimen, 
they  must  ultimately  either  degenerate  or  become  malignant.  They  certainly 
have  not  become  malignant.  They  have  degenerated,  and,  in  the  process,  have  , 
formed  a  substance  which  stains  with  Sudan  III.  Such  a  degeneration  is  commonly 
to  be  met  with  in  endothelial  cells. 


ABERRANT   DEVELOPMENT   OF  THE   LEUCOCYTOZOON   SYPHILIDIS.  17 

It  should  be  borne  in  mind  that  Sequeira's  patient  was  seriously  affected  by  his 
disease,  and  died  of  it,  and  this  probably  accounts  for  the  reason  why  the  cellular 
infiltration  is  mainly  endothelial.  I  have  noticed,  in  examining  syphilitic 
lymphatic  glands,  that  the  severer  the  case  of  sj^jhilis,  the  more  endothelial  in 
character  the  infiltration,  and  the  less  lymphocytic  it  was.  The  histology  of  the 
sections  of  this  case  appears,  to  me,  to  be  extremely  similar  to  that  met  with  in 
very  severe  cases  of  syphilis,  and,  in  nn^  opinion,  the  section  represents  a 
granuloma,  which  is  most  probably  of  protozoal  origin. 

AVhether  the  parasitic  bodies  represent  the  asexual  stage  of  the  Leucoajtozoon 
syphilidis,  or  of  some  other  coccidium,  I  am  unable  to  saj*.  As  the  boy  had 
Diabetes  insipidus,  and  since  we  know  that  this  condition  is  commonly  met  in  con- 
genital syphilis,  it  is  very  suggestive  at  first  sight  that  this  case  is  an  acute  case 
of  syphilis,  in  which  only  the  asexual  stage  of  the  parasite  has  developed. 

When  more  light  has  been  thrown  upon  this  interesting  point,  the  question 
will  naturally  arise,  does  the  organism  develop  in  a  pecuhar  way,  because  the  patient's 
resistance  compels  it  to  do  so,  or  because  the  organism  conies  of  a  breed  that  never 
forms  male  and  female  gametes  ? 

If  the  syphihtic  organism  is  cultured,  one  knows  that  only  the  Spirocliaeta 
pallida  grows,  and,  further,  that  it  will  grow  only  under  anaerobic  conditions.  It 
is  also  a  well  known  fact  that  the  processes  of  fertihsation  and  subsequent  develop- 
ment of  the  zygote  require  oxygen,  therefore  it  is  not  likely  that  bodies  other  than 
the  male  will  develop  under  anaerobic  conditions. 

This  point  is  mentioned  here,  because  the  distribution  of  oxygen  in  the  body 
might  have  an  effect  in  influencing  the  development  of  the  Leucocytozoon  syphilidis. 

As  will  be  seen  later,  when  the  chemistry  of  the  Leucocytozoon  syphilidis  is 
discussed  (Chapter  VI),  the  entrance  of  the  male  gamete  into  the  female  cell  causes 
certain  chemical  reactions. 

An  ovum,  during  and  after  fertilisation,  stains  in  vivo  with  the  methylene  red 
moiety  of  the  borax  methylene  blue,  and  this  signifies  the  formation  of  some  strongly 
reducing  substance,  which  was  not  present  prior  to  fertilisation. 

If  the  same  cells  be  examined  in  fixed  specimens,  it  is  found  that  the  fertilised 
female  cell  has  a  greater  affinity  for  basic  dyes.  This  indicates  that  the  reducing 
substance  is  of  an  acid  nature. 

Loeb^  found  that  a  fertilised  ovum  takes  up  neutral  red  more  readily  than 
an  unfertilised  ovum  does.  Neutral  red  is  a  base  ;  therefore  another  point  is 
gained  in  favour  of  the  view  that,  during  fertilisation,  there  is  an  increase  of  acid 
in  the  female  cell. 

This  acid  appears  to  be  of  fundamental  importance,  since  the  slightest  alteration 

B 


18  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF    SYPHILIS. 

in  the  hydroxyl-iou  couceiitration  of  the  fluid,  in  which  the  process  of  fertilisation  is 
taking  place,  is  sufficient  to  check  further  development. 

Loeb,  in  his  most  fascinating  work  on  artificial  parthenogenesis,  found  that  the 
female  cell  did  not  develop  a  mantle  until  he  had  added  acetic,  propionic,  or  butyric 
acid  to  the  sea  water  in  which  the  cell  was  developing. 

Mineral  acids  would  not  take  the  place  of  the  above-mentioned  monobasic 
fatty  acids,  except  when  sodium  acetate  or  sodium  butyrate  was  added. 

The  action  of  the  mineral  acid  is  to  break  up  the  salt,  and  set  free  a  fatty  acid  ; 
therefore  it  is  clear  that  fatty  acids  play  an  important  role  in  fertilisation. 

There  is  little  doubt  that  salts  also  exert  an  influence  upon  the  process  of 
fertilisation,  for  instance,  potassium  and  calcium  salts  have  a  stimulating  effect. 

Although  these  are  chemical  points,  I  mention  them  here.  I  do  so  in  order  to 
show  how  important  certain  chemical  substances  are,  for  one  of  the  most  important 
functions  in  the  development  of  any  organism  in  which  there  are  male  and  female 
bodies.  This  also  shows  how  little  is  the  alteration  required  to  upset  the  natural 
sequence  of  events. 

I  have  also  laid  great  stress  upon  the  question  of  aberrant  development,  because, 
if  the  body  can  change  the  mode  in  which  the  organism  develops,  we  might  be  able 
to  find  out  how  it  is  done,  and  in  this  way  either  find  a  preventive  against  the  disease, 
or  a  cure  which  is  more  certain  than  any  which  we  have  at  present,  and  what  is 
still  more  important,  we  may  be  able  to  give  aii  exact  prognosis  in  those  cases  in 
which  we  can  see  the  primary  sore. 

Since  the  above  was  written  I  have  had  a  case  under  my  care,  which  I  take 
to  be  one  of  coccidiosis,  in  which  the  coccidium  is  certainly  not  the  Coccidium 
sypkilidis. 

Case  2. — The  patient,  a  big  and  healthy-looking  man,  aged  22,  consulted 
me  for  a  rash  on  his  elbows  and  penis.  When  the  rash  appeared  the  patient  was 
stationed  in  the  North-West  Frontier  Province  (India),  and  the  follo\A;ing  is  the 
history  of  the  case  : — 

In  August,  1914,  the  patient  was  playing  hockey,  when  he  fell  and  cut  both 
knees  and  the  right  elbow.  A  dressing  was  applied  to  the  knees,  but  as  the  elbow 
wound  was  trivial  no  attention  was  paid  to  it.  The  knees  healed  quickh-,  but 
although  the  wound  healed  in  time  on  the  elbow,  a  rash  developed  outside  it,  and 
this  has  been  gradually  spreading  since.  In  September,  1914,  the  patient  had 
what  he  called  a  "  go  of  temperature,"  whicl  lasted  for  three  weeks.  The  patient 
had  never  had  fever  before,  so  the  diagnosis  made  at  that  time  was  fever  following 
a  frontier  sore.  Many  doctors  saw  the  sore  on  the  elbow,  and  most  were  of  the 
opinion  that  it  was  a  frontier  sore. 


Section  of  a  papule  from  a  case  of  Cvrcidlos'is  Avenerea  magnified  fifteeu  times. 
The  papule  is  seeu  to  be  situated  in  the  corium,  to  be  perfectly  circumscribed,  aud 
to  have  produced  uo  reaction  iu  its  jjeriphery. 


Plate  15. 


Facing  p.  18. 


PHUTUGllAPHS. 
X    1500 


Tru|iliozi.)iti- 


First  division  of  tiuiilio/.(.itc 


Development  of  tropliozoite  into  niorozoito. 


Plate  IC. 


Folhu$  Plate  15. 


ys 


..^^p 


^*  #  ^' 


Dt'veltipmi.'iit  L'f  irn'rozuitu  iutu  spores. 


i 


lutrncrllnhir  ili-vi'Iopinoiit  of  .sporor^ 


,n 


ExtracL'Uiibir  ilrvL'lopnu'ut  of  sxiores. 


Platk  17. 


Fullous  Plate  16. 


Plate  IS. 

Section  through  a  papule  froui  a  case  of  Coccidiosis  Avcncrca  (vide  Plate  15) 
stained  with  pyronui  and  methyl  green. 

A.  Spore  cyst. 

B.  Trophozoite  in  an  endothelial  cell. 

C.  Ballooned  endothelial  cell. 

D.  Spore  cyst  in  an  endothelial  cell. 

E.  K.  Foam  cells. 

F.  First  subdivision  of  trophozoite  in  an  endothelial  cell. 

G.  The  same,  but  the  body  is  extracellularly  situated. 
H,  L.  Binary  fission  of  trophozoite  in  endothelial  cells. 
J.  Trophozoites  extracellularly  situated. 


Folhivs  riaic  17. 


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Plate  18 


ABERRANT    DEVELOPMENT    OF   THE    LEUCOCYTOZOON    SYPHILIDIS.  10 

111  November,  1914:,  a  rash  appeared  on  the  penis,  and  a  month  later  the  left 
elbow  became  affected.  The  patient  was  treated  with  arsenic  internally,  and 
various  ointments  were  apphed  locally  without  any  result. 

The  lesion  on  the  right  elbow  was  a  little  bigger  than  a  five-shilling  piece ;  it 
was  purple-blue  coloured,  slightly  crusted  in  parts,  and  here  and  there  were  small 
depressed  scars.  The  patch  looked  not  unlike  a  Sarcoid.  Outside  the  patch  were 
several  irregularly  distributed  but  discrete  papules.  The  papules  were  about  the 
size  of  a  hemp-seed,  red-brown  in  appearance,  with  somewhat  of  a  transparent 
look,  hke  the  apple-jelly  nodules  in  lupus.  Some  of  the  papules  were  crusted,  a 
few  had  coalesced,  but  the  base  upon  which  they  were  situated  was  not  inflamed. 
The  rash  on  the  penis  and  on  the  left  elbow  was  papular,  and  indistinguishable  from 
the  papules  just  described.  The  papules  on  the  penis  affected  the  glans,  the 
corona  and  the  under-surface  of  the  prepuce.  WTien  the  under-surface  of  the 
prepuce  was  stretched  several  papules  were  seen  to  be  developing,  so  a  portion  of 
the  tissue  in  this  region  was  excised  for  a  microscopical  examination. 

The  patient  had  no  enlargement  of  his  lymphatic  glands,  nothing  else  abnormal 
could  be  discovered,  he  had  never  had  sexual  connection,  and  the  Wassermann 
reaction  was  negative  in  all  dilutions. 

Thinking  the  case  was  one  of  an  infective  granuloma,  and  probably  protozoal 
in  origin,  I  gave  the  patient  potassium  iodide  internally  and  unguentum  iodex 
externally,  with  the  result  that,  in  four  days'  time  there  was  a  very  distinct 
improvement. 

Histological  examination  of  an  early  papule. — Situated  in  the  deeper  layers  of  the 
corium  is  a  circular  cellular  infiltration,  about  1  mm.  in  diameter  (Plate  15),  The 
mass  is  perfectly  circumscribed,  and  there  is  no  surrounding  cellular  infiltration.  The 
mass  may  be  said  to  consist  of  three  parts  :  an  outer  layer  of  plasma  cells,  then  a 
layer  of  mixed  plasma  cells,  lymphocytes  and  endothelial  cells,  while  the  centre 
is  mainly  occupied  by  lymphocyte-producing  endothelial  cells.  Hence  the  mass 
was  not  unlike  a  lymphoid  follicle,  in  a  chronically  inflamed  lymphatic  gland. 

Mainly  in  the  intermediary  zone  were  to  be  found  some  intracellular  bodies, 
which  were  markedly  pjToninophile,  suggesting  at  once  that  they  were  parasitic. 

The  cell  affected  was  the  endothelial  cell,  and  the  following  are  the  phases  which 
could  be  discerned  (Plates  16,  17,  18) : — 

1.  A  bright  pyroninophile  mass  lying  in  its  own  unstained  protoplasm,  and  the 
whole,  situated  in  a  sac,  outlined  by  the  edge  of  the  protoplasm  of  the  endothelial 
cell,  and  in  one  part  by  the  concave  inner  surface  of  the  nucleus  (Trophozoite). 

2.  An  inclusion  body  in  which  the  pyroninophile  mass  had  become  divided 
into  two  (Merozoite). 

b2 


20  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF    SYPHILIS. 

3.  Inclusion  bodies  in  which  the  pyroninophile  masses  had  further  divided 
into  four,  eight,  and  so  on  (Spores). 

The  further  developed  was  the  inclusion  body,  the  more  degenerated  was  the 
endothelial  cell,  so  that  when  the  body  had  formed  what  appeared  to  be  spores, 
it  looked  as  if  it  were  extracellular.  The  inclusion  bodies  are  ojDtically  active,  and 
give  the  same  micro-chemical  reactions  as  the  phases  of  the  Leucocytozoon  sypMlidis, 
to  the  asexual  stage  of  which  they  closely  correspond. 

From  what  has  been  said  about  this  case,  the  most  reasonable  explanation 
to  offer  would  be,  that  the  organism  entered  the  wound  on  the  right  elbow  from  the 
earth,  developed  in  situ,  gained  entrance  to  the  circulation,  caused  fever,  and  then 
settled  down  in  various  areas  to  produce  lesions.  Considering  how  common 
coccidiosis  is  in  animals,  it  is  surprising  that  many  varieties  have  not  already  been 
described  in  man.  Just  as  sporotrichosis  has  laid  claim  to  some  cases  of  infective 
granuloma,  which  were  wrongly  diagnosed  as  syphilis,  coccidiosis  will  probably  soon 
be  found  to  do  the  same.  In  the  meantime,  the  name  of  Coccidiosis  avenerea  can 
be  given  to  those  cases  of  coccidiosis,  in  which  the  Leucocytozoon  syphilidis  is  not 
the  cause. 

1  McDonagh  (1914),  "  Brit.  Journ.  of  Dermatol.,"  xxvi.  1. 

2  McDonagh  (1914),  "  Brit.  Journ.  of  Dermatol.,"  xxvi,  85. 
'  Loeb,  "  Handbuch  der  Biochemie,"  ii,  80. 

*  Sequeira  (1914),  "  Brit  Journ.  of  Dermatol.,"  xxvi,  20,  332. 


o 


o 


o 


€      ^ 


10. 


12. 


Q 


13. 


14. 


>m 


IG. 


17. 


4,^ 


18. 


^/ 


19. 


0 


20. 


? 


■_'l. 


Lorlirs  seeu  in  rico  staiufd  with  borax  mi-ili\irii<'  hliic  in  imnual  ami  iullaiiu'd  ylauds. 

1-14  arc  developing  lymphocytes. 

1.").  10  ;ire  developing  granular  leucocytes. 

17,  18  are  red  blood  corpuscles. 

11)-"21  are  adult  leucocytes. 


Platk   1!). 


Facing  ;>.  20. 


CHAPTER  IV. 

ERRORS   TO   BE   AVOIDED   IN   EXAMINING   SYPHILITIC    OR    OTHER 

MATERIAL. 

It  may  be  as  well  to  mention  here  the  various  pitfalls  which  must  be  avoided, 
before  one  is  able  to  discriminate  normal  from  parasitic  cells. 
I. — In  vivo. — 

1.  Dark-staining  motile  dots,  which  are  either  bacteria  or  granules  from  leuco- 
cytes, are  frecjuently  to  be  seen.  As  a  rule  they  are  smaller  than,  and  do  not  stain 
so  deeply  as  the  sporozoites. 

2.  Circular  bodies,  of  all  sizes  from  1  to  7  microns,  are  invariably  to  be  found 
in  every  inflamed  tissue.  They  superficially  resemble  the  female  garaetocytes, 
but  may  be  distinguished  by  the  fact  that  they  contain  no  chromatin  network. 
The  darkly  staining  masses,  of  which  they  are  made  up,  are  mostly  situated  in  the 
circumference  of  the  cell  itself,  so  that  one  or  more  of  these  darkly  stained  masses 
will  be  crescentic  in  shape.  From  Plate  19,  it  will  be  noticed  that  there  is  a  close 
resemblance  between  the  mature  lymphocytes  and  the  small  circular  bodies  with 
the  crescentic  masses,  since  in  both  the  most  deeply  stained  part  of  the  lymphocyte 
and  tiny  body  is  the  periphery.  In  the  former,  the  periphery  may  be  stained  in  its 
entirety,  or,  more  generally,  irregularly,  with  a  preference  for  one  pole,  where 
deeply  staining  masses  are  to  be  found,  which  ultimately  become  extracellular. 
I  think  it  is  highly  probable  that  the  small  bodies  referred  to  are  immature 
lymphocytes.     (For  further  details,  vide  Chapter  XL VI.) 

3.  Small  granular  cells,  varying  in  size,  Hke  the  immature  lymphocytes,  might  be 
mistaken  for  small  spore  cysts  (Plate  19  (15,  16) ).  The  granules  in  the  immature 
leucocytes  are  smaller  than  the  sporozoites  in  the  spore  cyst,  less  actively  motile, 
not  so  metachromatic,  and  they  prefer  the  methylene  red,  to  the  methylene  violet 
moiety  of  the  borax  methylene  blue.  These  cells  are  probably  embryo  mast  cells 
(vide  Chapter  XL VIII). 

4.  The  fertilised  female  cell,  or  zygote,  might  possibly  be  mistaken  for  cells 
of  the  same  size,  which  also  have  an  affinity  for  methylene  red. 


22  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   SYPHILIS. 

If  these  cells  are  closely  studied,  it  will  be  noticed  that  the  affinity  for  methylene 
red  is  very  much  more  pronounced  than  it  is  in  the  case  of  the  parasitic  cells.  More- 
over, other  cells,  both  larger  and  smaller,  will  be  seen  to  exhibit  the  same  phenomenon, 
and  finally,  hardly  any  two  of  the  cells  are  exactly  aUke  ;  some  have  no  nucleus, 
others  have  their  chromatin  distributed  unevenly  about  the  cell,  either  in  small  masses 
or  in  strands  (Plate  20).  These  cells  will  later  be  found  to  be  degeneration  forms 
of  plasma  cells,  or,  in  short,  aminoplasma  cells  {vide  Chapter  VI). 

5.  Female  gametes  might  possibly  be  mistaken  for  a  certain  form  of  red  blood 
corpuscle,  the  centre  of  which  stains  with  the  same  dyes  as  does  the  nucleus  of  the 
parasitic  cell  (Plate  19  (18)  ).  These  red  blood  corpuscles  are  poor  in  haemoglobin, 
therefore  the  similarity  between  them  and  the  female  gametes  becomes  the  closer. 
The  following  points  will  serve  to  enable  a  distinction  to  be  made.  The  red  blood 
corpuscles  are  found  only  in  cases  of  pronounced  anaemia.  Their  staining  is  imeven, 
i.e.,  in  some  parts  it  is  very  faintly  marked,  while  in  others  it  is  deep.  Occasionally, 
here  and  there,  an  area  may  be  seen  which  has  taken  the  methylene  red  and  not  the 
methylene  violet  part  of  the  stain.  Finally,  the  stained  portion  may  be  in  the  form 
of  strands,  or  dots,  or  masses,  not  unlike  that  seen  in  the  aminoplasma  cells. 

II. — Fixed. — Endothehal  cells  which  contain  circular  masses  of  varying  sizes 
in  their  j)rotoplasm  may  be  mistaken  for  connective  tissue  syphilitic  bodies.  The 
cells  ultimately  burst,  and  these  masses  escape.  It  is  in  Giemsa-stained  specimens, 
and  in  sections,  that  these  masses  are  most  likely  to  be  mistaken  in  this  way.  In 
the  case  of  the  former,  no  bodies  should  be  taken  for  parasitic,  unless  they  have  a 
background,  which,  in  my  specimens,  closely  resembles  the  colour  of  a  red  blood 
corpuscle.  In  sections,  the  distinction  is  more  apparent.  The  endothelial  masses 
stain  a  dazzling  transparent  red  (pyronin),  and  look  as  if  they  had  no  depth  in 
them  ;  the  centre  is  usually  clear,  or,  it  woidd  be  better  to  say  that,  the  most  deeply 
stained  part  of  the  mass  is  the  periphery ;  furthermore,  some  of  the  masses  stain  green 
(methyl  green),  which  is  some  evidence  of  their  not  being  parasitic  {vide  Chapter  VI 
and  Plate  "21).  Far  and  away  the  most  distinguishing  feature  is  the  fact,  that  the 
syphilitic  bodies  are  massed  together  in  one  clear  encapsuled  space,  while  the 
endothelial  masses  are  scattered  irregularly  about  the  cell.  The  syphilitic  bodies, 
as  will  be  seen  from  Plate  1,  have  a  rose-pink  to  red  background,  with  their  nuclear 
structure,  situated  more  or  less  at  one  pole,  appearing  eccentrically  placed,  and 
very  deeply  stained,  sometimes  to  a  very  dark  red,  or  even  brown.  Most  of  the 
syphilitic  bodies  have  a  clear  space  or  halo  surrounding  them. 


4 


ik 


1. 


^ 


2/iD 


•t*c^i 


\ 


^ 


Q^ 


^^ 


10, 


i  v^-s^^^. 


1-2. 


lo. 


Varii,>iis  forms  of  ainiooplasma  colls  to  be  mot  with  in  hi  vivo  staininj?  with  borax  iiiotliylone  blvio 

from  any  plasiuomatoiis  losion. 


Plate  20. 


Facmg  p.  22. 


PHOTOGRAPHS. 
X    1500 


An  eudotliolial  cell  iu    a  flxed  section  from  a  lympliatic  gland.      Tlio 
lymphocytes  iu  the  developing  granoplasm  of  the  coll  are  clearly  discernible. 


This  is  a  later  stage  of  tlie  pri'i-.Mling-,  in  wliicli  most  of  the  lym|ihcieyti's 
to  be  formed  have  been  formed  and  Irft  tlir  cell.  The  endothelial  ell  iu 
consequence  has  begun  to  degeuiTale. 


Platk  21. 

Fnllmis  Villi,-  211. 


CHAPTER  V. 
ARGUMENTS  AGAINST  LEUCOCYTOZOON  SYPHILIDIS. 

I  may  here  mention  the  objections  which  have  been  raised  to  my  discover}-  of 
the  life-cycle.  These  objections  are  purely  theoretical,  for  no  observer,  other 
than  the  two  already  mentioned  (Page  6),  has  attempted  to  repeat  any  of  the 
work. 

The  objections  which  have  been  raised  can  be  quite  shortly  mentioned. 

It  is  contended  that  the  Spirochaefa  pallida  has  been  obtained  in  pure  culture, 
and  that  animals  have  been  infected  with  such  cultures.  I  have,  however,  been  able 
to  culture  the  Spirochaeta  pallida,  and,  from  my  experiments,  it  is  evident  that  the 
Spirochaeta  pallida  in  culture  develops  cxtracellularly.  It  is  possible  to  lay  too 
much  stress  upon  cultures,  especially  in  the  case  of  protozoa.  With  bacteria  and 
fungi,  the  greatest  morphological  differences  exist  between  the  same  organism  in 
the  body,  and  in  cultures,  not  to  mention  the  variations  produced  by  the  different 
media  upon  which  they  are  grown.  The  difference  is  hkely  to  be  greater  when  the 
growth  in  culture  of  a  highly  developed  organism  like  a  protozoon,  is  compared 
with  its  growth  in  vitro. 

The  statement  that  animals  can  be  infected  with  syphilis  from  cultures  of  the 
Spirochaefa  pallida,  is  no  objection  to  my  life-cycle,  for  the  following  reasons  : — 

(1)  In  many  instances,  if  a  sufficient  quantity  of  a  certain  organism  be  injected 
into  an  animal,  inflammation  will  result,  and  some  of  the  organisms  may  be  found 
in  the  urine  and  blood-stream.  This  is  not  evidence  that  the  animal  is  suffering 
from  the  specific  disease  caused  by  that  organism. 

It  must  not  be  forgotten  that,  if  a  sufficient  quantity  of  wax  or  fat  be  injected 
into  a  rabbit's  testicle,  fine  particles  of  the  same  may  be  found  later  in  the  blood- 
stream and  in  the  urine. 

(2)  Considering  the  resistance  of  the  spores,  and  their  small  size  compared  with 
that  of  the  spirochaetae,  they  can  be  easily  overlooked  and  injected  with  the  latter, 
when  only  spirochaetae  were  .supposed  to  be  present.  If  looked  for  in  cultures 
of  the  Spirochaeta  pallida,  these  small  bodies  can  alwaj's  be  found.     Therefore, 


24  THE    BIOLOGY,    CLINICAL   ASPECT   AXD   TREATMENT   OF   SYPHILIS. 

what  is  happening  in  the  test  animal's  body,  may  be  no  more  than  what  is  taking 
place  in  a  culture  tube. 

The  other  points  are,  that  the  phases  described  and  depicted  are  cell  degenera- 
tions, nuclear  degenerations,  or  korpereigene  structures.  The  next  chapter  on 
the  chemistry  of  the  Leucocytozoon  syphilidis  will  show  that  these  views  are 
untenable. 

Still  another  argument  against  my  view  being  correct  was,  that,  in  some  pro- 
tozoal diseases,  an  intermediate  host  was  necessary  for  the  full  development  of 
the  organism,  e.g.,  malaria,  trypanosomiasis,  etc.  Because  an  intermediate  host, 
such  as  the  mosquito,  has  been  found  necessary  for  the  complete  development  of 
the  Plasmodium  nialariae,  it  does  not  follow  that  an  intermediate  host  should  be 
required  by  all  protozoa.  This  searching  for  an  intermediate  host  in  all  protozoal 
diseases  is  doubtless  hampering  many  discoveries.  Syphilis  is  a  disease  conveyed 
from  person  to  person,  and  therefore  it  cannot  be  compared  with  malaria,  which 
cannot  be  spread  in  this  wise. 

Owing  to  the  difficulty  in  doing  animal  experiments  in  England,  I  decided  to 
try  an  entirely  new  path,  and  to  attempt  to  prove,  by  chemical  means,  that  the 
bodies  described  could  not  be  protoplasmic  or  nuclear  degenerations,  or,  as  Hoffmann 
called  them,  horpereigene  structures.  In  this  work  I  was  ably  assisted  by  R.  L. 
Mackenzie  Wallis,  and  we  received  valuable  assistance  from  Unna's  writings  upon  the 
biochemistw  of  the  skin. 


CHAPTER  VI. 
CHEMISTRY  OF  THE  LEUCOCYTOZOON  SYPHILIDIS. 

The  Physical  and  Chemical  Properties  of  the  Staining  Reagents  Used. 

In  all  micro-chemical  iiivestigation.s,  full  consideration  must  be  given  to  the 
chemical  and  physical  properties  of  the  staining  reagents,  before  any  conclusions 
are  drawn  as  to  the  chemical  nature  of  the  structures  under  observation.  Ahnost 
all  the  members  of  the  group  of  dyes  are  colloidal  in  nature,  that  is  to  say,  they  do 
not  readily  diffuse  through  animal  membranes.  Like  other  colloids,  they  have  high 
molecular  weights,  and  they  are  amorphous.  In  solution  these  dyes  form  typical 
colloidal  suspensions,  the  size  of  the  particles  varying  in  different  cases  ;  consequently 
some  stains  appear  quite  homogeneous,  whilst  others  show  the  well-marked  characters 
of  suspensions.  Further,  many  dyes  are  eliminated  by  filtration,  and  they  may  be 
separated  by  this  means ;  for  example,  methylene  blue  occurs  in  the  urine  after 
subcutaneous  injection. 

Owing  to  their  colloidal  nature,  the  small  particles  of  a  dye  in  suspension  become 
electrically  charged,  and,  for  convenience,  dyes  may  be  divided  into  negatively  and 
positively  charged  colloids.  The  negatively  charged  colloidal  particles  of  a  dye 
will,  therefore,  show  electrical  migration  to  the  anode,  whilst  positively  charged 
colloids  will  travel  towards  the  kathode.  It  follows  from  this  also,  that  on  mixing 
a  positive  dye  with  a  negative  dye,  the  charges  will  be  neutrahsed,  and  the  resulting 
colloidal  mixture  will  then  exist  in  an  uncharged  condition ;  e.g.,  the  eosine-methylene 
blue  mixture,  the  former  being  negatively  charged  whilst  the  latter  is  positively 
charged. 

The  most  notable  feature  common  to  all  dyes  is  that  they  exhibit  the  pheno- 
menon of  adsorption  (Bayhss  ®).  By  adsorption  is  meant  a  "  combination  "  between 
two  substances  which  is  not  strictly  in  the  nature  of  a  chemical  union,  that  is  to  say, 
in  which  there  is  no  direct  proportionality  between  the  concentration  of  the  solution 
and  the  amount  adsorbed.  There  is  some  kind  of  physico-chemical  affinity  between 
the  bodies  adsorbed,  and  those  which  take  them  up,  but  this  affinity  is  more  of  a 


26  THE    BIOLOGY,    CLINICAL   ASPECT    AND    TREATMENT   OF    SYPHILIS. 

mechanical  than  of  a  tnie  chemical  nature.  To  take  an  example,  if  a  series  of 
solutions  of  Congo  red  be  taken,  of  different  concentrations,  and  the  same  amount 
of  filter  paper  be  placed  in  each,  a  part  of  the  dye  is  taken  up,  but  in  relatively 
larger  proportions  in  the  more  dilute  solutions  of  the  dye. 

There  are,  however,  instances  where  the  combination  of  the  dye  with  the  material 
acted  upon,  is  in  the  nature  of  a  true  chemical  combination  ;  but  these  are  rather 
exceptional  cases,  e.g.,  the  staining  of  nuclei  with  rongalit  white. 

The  presence  of  electrolytes  is  a  most  important  factor  in  the  process  of  pre- 
paring histological  specimens.  As  regards  their  adsorptive  capacities,  the  dyes, 
as  a  whole,  are  very  sensitive  to  electrolytes,  and  the  effect  appears  to  be  propor- 
tional to  their  colloidal  nature.  Electro-negative  dyes,  like  Congo  red,  are  increased 
in  adsorptive  power  by  the  addition  of  kations,  such  as  lithium,  potassium,  sodium, 
ammonimn,  magnesium  and  calcium.  On  the  other  hand,  anions  such  as  hydroxyl, 
acetate,  chloride,  oxalate,  sulphate  and  phosphate  depress  adsorption.  With 
electro-positive  dyes,  such  as  toluidine  blue,  the  reverse  is  the  case,  namely,  anions 
increase,  and  kations  depress  the  adsorptive  capacity.  The  effect  of  electroh^tes, 
however,  is  much  more  marked  in  the  case  of  kations  than  in  that  of  anions.  The 
salts  of  those  heavy  metals  which  form  positively  charged  colloidal  hydroxides — 
for  example,  iron — have  a  very  powerfid  effect  on  the  adsorptive  capacity  of  electro- 
negative dyes.  In  every  case,  the  ion  promoting  adsorption  of  the  dye  is  carried 
down  with  it. 

If  attention  be  now  paid  to  histological  preparations,  perhaps  it  may  be  possible, 
in  the  light  of  these  observations,  to  interpret  the  changes  induced  in  the  act  of 
staining.  In  the  living  cell,  the  substance  to  be  stained  has  a  negative  charge, 
for  the  reaction  of  the  tissues  always  tends  towards  the  alkaline  side  of  neutrahty. 
It  is  known  that  protein  solutions,  in  an  alkaline  mediimi,  are  always  negatively 
charged  ;  it  follows,  therefore,  that  hving  cells  will  take  up  basic  dyes,  and  that 
electrolytes  are  not  essential  to  the  process.  When  the  cells  die,  the  electrolytes 
attached  to  the  protein  constituents  of  the  cell  are  split  off,  with  the  result  that  the 
cells  now  readily  take  up  acid  dyes.  Farther,  the  fixation  of  a  dye  is  facilitated  by 
heat,  and  this  fact  has  been  utihsed  in  Altmann's  method  of  acid  fuchsin  staining. 
Mayer  has  also  shown,  that  the  affinity  of  the  Nissl  bodies  of  nerve  cells  for  basic 
dyes  is  destroyed  by  previous  treatment  with  neutral  salts.  This  ob.servation 
further  emphasises  the  importance  of  electrolytes  in  the  process  of  staining. 

If  similar  observations  now  be  made  upon  the  syphilitic  parasite,  it  can  be  seen 
whether  the  results  obtained  may  be  interpreted  in  the  light  of  these  views  of  staining. 
In  the  first  place,  chief  consideration  will  be  given  to  the  two  principal  stains  used, 
viz.,  pyronin  and  methyl  green.     Both  these  dyes  are  positively  charged  colloids. 


CHEMISTRY    OF  THE    LEUCOCYTOZOON    .SYPHILIDIS.  27 

and,  in  consequence,  their  staining  action  will  be  facilitated  by  the  presence  of 
anions,  particularly  of  hydroxyl  and  siilphanion.  The  pyronin  will,  therefore,  act 
as  a  basic  dye  ;  and  this  explains  why  it  is  precipitated  by  nigi'osine  and  also  by 
diamine  green,  but  not  by  diazine  green.  By  considering  the  chemical  characters 
of  the  dyes  used,  and  by  reviewing,  in  the  light  of  this  knowledge,  all  the  results 
obtained,  it  is  obvious  that  much  useful  and  valuable  information  of  the  micro- 
chemistry  of  the  cells  under  investigation  may  be  gained.  The  specific  staining  pro- 
perties of  the  s}^hihtic  parasite  will  be  referred  to  again,  and  all  that  need  be  pointed 
out  here,  is  the  importance  of  regarding  pyronin  as  a  positively  charged  colloid, 
and  as  one  influenced  by  anions. 

The  Characters  of  the  Syphilitic  Bodies,  when  Stained  "  In  Yivo." 

The  simplest  and  best  way  to  use  a  reagent  for  vital  staining,  is  to  spread 
a  solution  of  it  on  a  shde  free  from  fat  and  alkali,  and  to  allow  this  to  dry  in  the  air. 
The  film  should  be  made  just  before  it  is  required,  and  should  not  be  kept  for  several 
days.  The  material  to  be  examined  is  placed  upon  a  cover  shp,  and  the  latter  is  so 
adjusted  to  the  shde  that  no  air  remains  between  them,  and  so  that  the  fluid  to  be 
examined  exudes  at  the  sides  as  little  as  possible.  Examination  is  possible  until 
the  fluid  has  dried,  that  is,  for  several  hours.  The  process  is  greatly  facilitated  by 
ringing  the  cover  shp  with  wax.  The  shdes  used  for  hanging  drop  preparations  are 
useless,  but  a  warm  stage  may  sometimes  be  employed  ■with  advantage. 

I  have  used  all  the  stains  which  have  been  from  time  to  time  advocated,  but 
I  have  not  obtained  the  results  promised  by  the  literature  on  these  stains.  I  may 
at  once  state  that  neutral  red,  neutral  violet,  Bismarck  brown,  auramine,  diazine 
green,  malachite  green,  tropaeohn  00,  and  Congo  red,  do  not  give  good  vital  staining. 
Owing  to  the  use  which  is  now  being  made  of  the  azo-dyes,  in  determining  the 
functional  activity  of  certain  cells  in  the  body,  I  tried  several  for  my  method  of 
staining  in  vivo,  but  with  poor  .success.  They  have  feeble  staining  i)roj)erties,  and 
are  general  protoplasmic  stains,  without  possessing  preferential  affinity  for  certain 
structures.  Moreover,  they  do  not  possess  metachromatic  properties.  The  dyes 
which  gave  the  best  results  were  aqueous  solutions  of  borax  methylene  blue,  Jjoly- 
chi'ome  methylene  blue,  brilhant  crystal  blue,  Nile  blue  sulphate,  and  alcoholic 
solutions  of  toluidine  blue,  thionine  and  azure  II.  The  disadvantage  of  the  alcoholic 
solutions  is,  that  they  must  be  well  diluted  before  use,  as  crystals  form  so  readilj- ; 
this  is  especially  the  case  with  thionine.  Azure  II  stains  deeply,  but  unfortunately 
it  has  no  metachromatic  properties.  The  intracellular  stages  are  perhaps  better 
depicted  by  the  alcoholic  stains  ;   but,  on  the  whole,  the  results  are  not  so  good  as 


28  THE    BIOLOGY.    CLINICAL   ASPECT    AND   TREATMENT   OF   SYPHILIS. 

when  the  aqueous  solutions  of  either  borax  methylene  blue  or  brilliant  crystal  blue 
are  used.  Of  the  last  two,  the  former  is  superior.  The  metachromatic  properties 
of  borax  methylene  blue  are  dependent  upon  the  basic  sodium  biborate.  The  latter 
acts  upon  methylene  blue  to  produce  both  methylene  violet,  which,  as  a  basic  dye, 
shows  affinity  for  acid  substances,  and  methylene  red,  which  is  an  acid  dye,  and  so 
shows  affinity  for  basic  substances. 

I  tried  various  other  bases  with  methylene  blue,  with  the  hope  of  obtaining 
greater  metachromatic  action  by  substituting  for  the  borax  a  base  of  higher  valency. 
For  this  purpose  colloidal  aluminium  hydroxide  was  employed.  The  methylene  blue 
remained  unaltered,  no  doubt  owing  to  the  fact  that  the  aluminium  hydroxide 
did  not  contain  sufficient  free  hydroxyl-ions,  and  that  it  was  itself  an  unstable 
colloid,  which  therefore  had  no  action  upon  the  positively  charged  methylene  blue. 

Borax  methylene  blue,  when  freshly  prepared,  has  practically  no  metachromatic 
action,  but,  the  longer  the  stain  is  kept,  the  more  this  property  increases.  Finally 
the  methylene  red  becomes  the  stronger  dye,  and  stains  the  cells  just  as  the  methylene 
violet  does.  Borax  methylene  blue  appears  to  be  at  its  best  when  it  has  been  kept 
for  a  year  or  two.  As  the  methylene  red  scarcely  comes  into  play  in  the  fresh 
solutions,  no  harm  is  done  by  adding  0'  1  grm.  eosine  to  100  c.c.  borax  methylene  blue, 
for  a  true  chemical  compound  results.  The  eosine  picks  out  the  granules  in  the  poly- 
morphonuclear leucocytes,  and  it  brilhantly  stains  the  eosinophile  granules,  but  does 
not  afiect  any  one  of  the  stages  of  the  syphihtic  organism.  I  learnt  that  the  sj^hiUtic 
organisms  contained  lecithin  in  the  form  of  a  lecithin-globulin  complex.  I  was 
aware  of  the  affinity  of  this  complex  for  dextrose,  so  it  struck  me  that  it  might  be 
possible  to  increase  the  staining  properties  of  the  organism,  by  adding  dextrose 
to  borax  methylene  blue.  Although  the  dextrose  did  not  carry  the  colloidal  dye 
particles  to  the  organism,  it  nevertheless  was  taken  up  by  every  cell  which  contained 
the  lecithin-globulin  complex,  since  the  protoplasm  of  such  cells  swelled  and  absolutely 
refused  to  stain,  but,  owing  to  the  swelling,  they  were  as  easily  discernible  as  if  they 
had  stained,  consequently  the  plasma  cells  and  syphihtic  bodies  could  be  well  studied, 
as  their  nuclei  were  not  prevented  from  staining.  I  witnessed  the  act  of  impregna- 
tion in  a  dextrose-borax  methylene  blue  specimen,  so  I  was  able  to  compare  it  with 
what  I  had  previously  seen.  The  nucleus  of  the  female  appeared  to  float  about, 
surrounded  by  the  clear  ring  of  mistained  protoplasm  ;  when  first  seen,  one  end  of 
the  spirochaeta  had  already  entered,  as  one  extremity  was  fixed  to  the  nucleus  ; 
the  spirochaeta  was  also  thickened  (due  to  the  dextrose).  The  one  end  of  the 
spirochaeta  remained  fixed  to  the  female  nucleus,  and,  in  spite  of  impact  with  other 
cells  in  its  progress,  it  remained  attached  to  the  sanie  spot,  but  did  not  enter  any 
further.      Suddenly  the  female  cell  became  stationary  and  the  SpirocJiaeta  pallida 


CHEMISTRY    OF   THE    LEUCOCYTOZOON   SYPHILIDIS.  29 

completely  entered  it,  but  55  iniinites  had  elapsed  before  this  hai:)pened.  No  further 
change  was  noticed  in  the  female  cell,  as  it  had  not  stained  very  well,  but  about  four 
minutes  later  it  became  very  active  and  discharged  a  clear  non-staimng  polar  body, 
which  seemed  to  be  emitted  with  some  force.  A  few  seconds  later,  another  clear 
polar  body  was  extruded,  and  then  the  female  cell  came  to  a  standstill  again.  It  is 
possible  that  the  dextrose  made  these  jjolar  bodies  appear  bigger  than  they  really 
were,  as  each  appeared  to  be  certainly  2-3  fj.  in  diameter. 

From  what  has  been  stated,  it  will  be  easily  seen  that  a  description  of  the 
syphilitic  organism  iji  vivo,  frona  its  reactions,  will  entirely  depend  upon  the  characters 
of  the  borax  methylene  blue  which  is  used.  Now,  as  impregnated  female  cells  do 
not  stain  with  eosine,  or  with  the  methylene  red  of  freshly  prepared  borax  methylene 
blue,  the  increase  in  the  basicity  resulting  from  impregnation  cannot  be  very  great. 
It  is  far  more  probable  that  little  change  in  reaction  occurs,  and  that  the  reason  for 
staining  with  methylene  red,  a  fact  which  I  have  frequently  observed,  is  due  to  an 
increase  in  the  reducing  action,  as  will  be  shown  later. 

The  sporozoites  may  remain  for  some  time  unstained,  or  they  may  immediately 
stain  a  dense  violet.  The  intracellular  phases  stain  late,  and  the  early  ones  show  an 
affinity  for  the  methylene  violet  moiety,  whilst  the  late  ones,  viz.,  the  coils,  take  up 
the  methylene  red.  The  females,  before  fertilization,  remain  unstained,  except  their 
chromatic  network  and  blepharoplasts,  which  immediately  stain  with  methylene 
violet.  The  Spirochaeta  pallida  stains  pink,  and  when  it  has  impregnated  a  female 
cell  and  when  the  whole  cell  has  come  to  a  sudden  standstill,  a  pink  diffuse  stain 
comes  over  the  cell  like  a  mantle.  The  sporozoites,  while  in  the  spore  cysts,  show  a 
greater  affinity  for  methylene  red  than  for  methylene  violet,  and  some  sj^ore  cysts 
are  seen  which  stain  distinctly  metachi-omatically. 

In  staining  in  vivo  with  a  negatively  charged  colloid,  it  follows  that  basic 
dyes  will  react  best,  and  this  has  been  found  to  be  the  case.  The  reason  why 
neutral  red,  neutral  violet,  Bismarck  brown,  auramine,  diazine  green,  malachite 
green,  tropaeoliu  00,  and  Congo  red,  were  found  not  to  give  good  results,  is  simply 
due  to  the  fact  that  they  are  negatively  charged  dyes,  and  therefore  they  cannot 
stain  cells,  which  contain  colloids  in  solution  with  a  negative  charge,  and  which 
exist  in  a  medium  on  the  alkaline  side  of  neutrality.  It  follows  that  good  staining 
can  be  obtained  only  by  using  dyes  with  a  positive  charge,  hence  the  reason  why 
borax  methylene  blue  and  polychrome  methylene  blue  serve  so  admirably,  for  it 
is  only  under  such  conditions  that  adsorption  can  come  into  play. 

Summary. — Basic  stains  are  the  most  suitable  for  in  vivo  work,  and,  of  these,  borax 
methylene  blue  is  the  best.  Owing  to  the  presence  of  a  lecithin-globuhn  envelope, 
the  syphilitic  bodies  can  be  made  to  stand  out  more  clearly  by  adding  dextrose 


30  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   SYPHILIS. 

to  the  stain.  The  varied  affinity  shown  by  the  different  bodies,  on  the  one  hand 
for  methylene  violet,  and  on  the  other  hand  for  methylene  red,  is  due  to  the  pre- 
valence of  a  substance  which  has  strong  reducing  properties  (lecithin-globulin), 
and  not  so  much  to  a  change  in  the  reaction. 

The  Characters  of  the  Syphilitic  Bodies  when  Stained  in  Fixed 

Specimens. 

Both  Pappenheim  and  Martin  Heidenhain  explained  the  specific  action  of 
methyl  green  for  chromatin,  as  being  due  to  the  breaking  down  of  the  weak  basic 
salt  by  the  strong  nucleic  acid  radicle.  The  nucleus,  however,  did  not  stain  with 
pyronin,  which  they  regarded  as  being  a  more  strongly  basic  salt.  As  a  matter  of 
fact,  since  methyl  green  is  a  triamino-stain,  it  is  by  far  a  stronger  base  than  the 
diamino-stain  pyronin,  the  basicity  of  which  is  also  diminished  by  its  extra 
oxygen  atom.  Furthermore,  acetic  acid  increases  methyl  green  staining,  and  if 
acids  combine  with  the  free  amino  group  of  the  salt,  acetic  acid  would  have  done 
this  before  the  nucleic  acid  could  do  so.  Therefore,  this  explanation  of  its  action, 
which  had  held  sway  for  some  years,  cannot  be  the  correct  one. 

A  stain  which  had  been  largely  used  by  Unna,,  namely,  rongalit  white,  was 
found  to  resemble  methyl  green  in  many  respects,  and  was  only  known  to  stain 
the  oxygen  positions  of  the  tissues. 

Rongalit  white  is  the  leuco-base  of  methylene  blue,  and  it  is  prepared  with 
sodium  sulphite  and  formalin.  It  is,  therefore,  a  colourless  and  basic  mixture, 
and  the  methylene  blue  is  only  brought  out  as  a  dye  in  the  presence  of  oxygen. 
As  rongalit  white  stains  the  nuclear  part  of  the  cell,  Unna  concluded  that  methyl 
green  also  picked  out  the  oxygen  foci  of  the  tissue,  and  that  it  was,  therefore,  a 
reduction-sensitive  stain. 

By  a  series  of  experiments,  Unna  showed  that  methyl  green  was  far  more 
sensitive  to  reducing  substances  than  methylene  blue  was,  and  that  malachite 
green  came  in  between,  but  that  such  reducing  agents  as  grape  sugar  and  hydroxyl- 
amine  were  without  effect,  i.e.,  they  did  not  decolourise  methyl  green.  Another 
difference  between  methyl  green  and  methylene  blue,  and  malachite  green  was, 
that  the  leuco-bases  of  the  last  two  could  be  reconverted  into  their  coloured  bases 
by  the  addition  of  hydrogen  peroxide,  but  this  could  not  be  done  in  the  case  of 
methyl  green. 

Until  Unna  enunciated  his  theory  of  staining  by  oxidation  and  reduction,  we 
were  under  the  impression  that  staining  depended  upon  reaction  ;  in  other  words 
that  acid  substances  stained  with  basic  dyes,  and  were  therefore  termed  basophihc  ; 
and   that  basic  substances  stained  with  acid  dyes,  and  were  therefore  termed 


~1 

vco-      \ 


Plate  22. — Twelve   Ready   Methods   for  DiPPERENTLiTiNG   the   Phases   or  the  Le 
CYTOzoox  SyriiiiJDis  in  Section. 

1. — Section  of  sypliilitic  lymphatic  gland,  fixed  in  50  per  cent,  alcohol,  and  stained 
with  equal  parts  of  freshly  prepared  1  per  cent,  solutions  of  potassium  ferricyanide  and  ferric 
chloride,  mixed  imnrediately  before  use.  The  syphilitic  body  is  a  zygote.  Owing  to  the  reducing 
action  of  the  parasitic  lipoid-globulin,  which  is  most  marked  over  the  nucleus,  the  protoplasm 
stains  a  light  Berlin  blue,  while  that  part  of  the  protoplasm  over  the  nucleus  stains  a  dark  Berlin 
blue.  The  other  cells  stain  green.  Aminoplasma  cells,  owing  to  the  strong  reducing  action 
they  exhibit,  because  of  the  tjTosine  they  contain,  also  stain  dark  Berlin  blue,  but  these  can 
easily  be  distinguished  from  the  sypliilitic  parasites.  The  female  gametocyte  is  indistinguishable 
from  a  plasma  cell,  because  the  reducing  action  of  the  lipoid-globulin  does  not  become  marked 
until  after  fertilisation. 

2. — Section  of  syphilitic  lymphatic  gland,  hardened  in  50  per  cent,  alcohol,  and,  befoio 
being  stained  with  pyronin  and  methyl  green,  left  for  twelve  hours  in  a  mixture  of  a  1  per 
cent,  solution  of  potassium  ferrocyanide  and  equal  parts  of  normal  acetic  acid.  If  the  tissue 
is  hardened  in  50  per  cent,  alcohol  and  treated  with  the  potassium  ferrocyanide  solution 
only,  every  trace  of  lipoid-globulin  vanislies.  If  the  tissue  is  hardened  in  absolute  alcohol  and 
treated  with  the  potassium  ferrocyanide  solution,  only  the  most  resistant  lipoid-globulin  remains 
behind.  The  addition  of  acetic  acid  to  the  50  per  cent,  alcohol  hardened  specimen,  prevents  the 
destruction  of  the  more  resistant  lipoid-globulin,  and  therefore  serves  as  an  excellent  means  of 
differentiating  the  Leiicocijlozoon  syphilidis.  The  phase  shown  in  this  specimen  is  the  binary 
fission  of  a  zygote.  Note  the  admirable  preservation  of  the  syphilitic  lipoid-globulin,  the  less 
preserved  pyroninophile  properties  of  the  nucleoli,  and  the  still  less  preserved  pyroninophile 
properties  of  the  protoplasm  of  the  plasma  cells. 

3. — Section  of  syphilitic  lymphatic  gland  fixed  in  absolute  alcohol,  and  treated  for 
twelve  hours  with  a  1  per  cent,  solution  of  potassium  ferrocyanide,  before  being  stained  with 
pjTTonin  and  methyl  green.  The  phase  shown  is  a  female  gametocyte.  It  should  be  noted  that 
the  protoplasm  of  the  plasma  cells  scarcely  stains,  and  that  even  a  small  portion  of  the  syphilitic 
lipoid-globulin  has  been  destroyed,  since  the  protoplasm  of  the  syphilitic  cell  stains  only  a  pale 
rose-pink  and  the  nucleus  a  deeper  red. 

4. — Section  of  syphilitic  lymphatic  gland,  fixed  in  50  per  cent,  alcohol,  and  treated  with 
normal  saline  for  twelve  hours,  before  being  stained  with  pyronin  and  methyl  green.  The  phase 
represented  is  a  spore  cyst.  In  the  spore  cyst  it  will  be  noted  that  three  bodies  are  stained  red, 
while  seven  smaller  bodies  are  stained  dark  green.  Three  bigger  bodies  stain  red,  because  they 
have  not  lost  their  lipoid-globulin  membrane.  They  are  therefore  sporoblasts.  The  smaller 
bodies,  which  have  lost  their  lipoid-globulin  membrane,  are  sporozoites.  The  lipoid-globulin 
of  the  plasma  cells  and  of  the  nucleoli  has  vanished. 

5. — Section  of  a  syphilitic  lymphatic  gland,  fixed  in  50  per  cent,  alcohol,  and  stained  with 
rongalit  white  II.  The  phase  sho\vn  is  a  female  gamete,  just  after  fertilisation.  It  will  be 
noted  that  the  protoplasm  of  the  plasma  cells  does  not  stain,  only  the  nuclei  and  the  nucleoli. 
The  protoplasm  of  the  syphilitic  phase  stains  pale  blue,  while  that  covering  the  nucleus  stains 
a  very  dark  blue,  much  darker  than  the  chromatin  of  the  nuclei  of  the  j^lasma  cells  and  of  their 
nucleoli.  This  shows  that  the  oxygen  content  of  the  syjihilitic  body  is  much  greater  than  that 
of  the  nuclei  or  the  nucleoli  of  the  other  cells. 

6. — Section  of  a  syphilitic  lymphatic  gland,  fixed  in  50  per  cent,  alcohol,  and  stained 
with  Ehrlich's  triaeid  stain.  The  phase  shown  is  a  developing  trophozoite  in  a  connective-tissue 
cell.  It  will  be  noted  that  the  protoplasm  of  the  plasma  cells  does  not  stain,  nor  do  their  nucleoli, 
with  the  acid  fuchsin,  while  the  protoplasm  of  the  syphilitic  j'arasite  does. 


7. — Section  of  a  syphilitic  lymphatic  gland,  fixed  in  absolute  alcohol,  and  stained  with 
pyronin  and  diazine  green.  The  phase  shown  is  a  female  gametocyte.  It  should  be  noted  that 
the  nucleus  of  the  sj-philitic  parasite  stains  with  pyronin,  while  the  nucleoli  of  the  other  cells 
stain  with  the  diazine  green.  Diazine  green  is  not  nearly  so  sensitive  to  reducing  substances  as  is 
methyl  green,  and  since  the  nucleus  of  the  syphilitic  cell  stains  ■nith  pjTonin,  while  the  nucleoli 
of  the  plasma  cells  stain  with  diazine  green,  it  jjroves  that  the  reducing  action  of  the  syphiUtie 
bodies  is  greater  than  that  of  the  normal  cells. 

8. — Section  of  a  syphilitic  lymphatic  gland,  fixed  in  absolute  alcohol,  and  stained  with  safra- 
nin  and  methyl  green.  The  phase  showni  is  a  female  gametooj'te.  It  should  be  noted  that  the 
syphilitic  body  shows  a  greater  affinity  for  safranin  than  does  the  protoplasm  of  the  plasma  cells. 
Further,  the  nucleoli  stain  with  methyl  green.  The  picture  presented  by  this  specimen  might 
at  first  sight  appear  paradoxical,  because  so  much  has  been  said  of  the  pyroninophile  properties 
of  the  Leucocytozoon  syphilidis.  Pyi'onin  is  a  basic  stain,  safranin  is  an  acid  stain.  As  the 
syphihtic  parasite  stains  so  well  with  safranin,  it  is  clearly  shown  that  amphoterism  only  plays  an 
insignificant  part  in  the  staining  of  fixed  material,  while  reducing  action  plays  a  greater  part. 
The  reducing  action  of  the  nucleoli  is  not  sufficient  to  overcome  their  basophilic  properties, 
consequently  they  stain  with  methyl  green.  In  the  syphilitic  parasite,  on  the  other  hand,  the 
reducing  action  of  the  lipoid-globulin  membrane  of  the  nucleus  so  strongly  outweighs  its  baso- 
philic properties,  that  it  stains  with  safranin  rather  than  with  methyl  green. 

9. — Section  of  a  sjrphilitic  lymphatic  gland  fixed  in  50  per  cent,  alcohol  and  treated  with 
human  serum  for  twenty  hours  before  being  stained  with  pyronin  and  methyl  green.  The 
phase  sho\\ii  is  a  spore  cyst.  It  will  be  noted  that  only  a  portion  of  the  lipoid-globulin  has  been 
destroyed,  wliile  that  of  the  plasma  cells  and  nucleoli  has  completely  vanished. 

10. — Section  of  syphilitic  lymphatic  gland,  fixed  in  50  per  cent,  alcohol  and  treated  for 
twelve  hours  with  25  per  cent,  alcohol,  before  being  stained  with  pyronin  and  methyl  green.  The 
phase  shown  is  a  trophozoite,  in  a  connective-tissue  cell.  It  should  be  noted  that  more  lipoid- 
globulin  has  been  destroyed  than  in  the  following  specimen,  that  the  protoplasm  of  the  syphihtic 
body  stains  with  about  the  same  intensity  as  that  of  the  plasma  cells,  while  the  lipoid-globulin 
covering  the  nucleus  is  still  markedly  pyroninophile.  As  some  of  the  lipoid-globulin  covering 
the  nucleus  has  been  destroyed,  one  sees  a  trace  of  the  chromatin  network  arrangement  of  the 
nucleus  in  an  early  trophozoite. 

II. — Section  of  a  s\-philitic  lymphatic  gland,  fixed  in  50  per  cent,  alcohol  and  treated 
with  50  per  cent,  alcohol  for  twelve  hours,  before  being  stained  with  pyronin  and  methyl  green. 
The  phase  shown  is  a  trophozoite,  in  a  connective-tissue  cell.  It  will  be  noted  that  the  proto- 
plasm of  the  plasma  cells  stains  better  than  in  the  preceding  specimen,  and  the  syphihtic  parasite 
also  stains  better,  but  comparing  it  with  the  following  specimen,  one  can  see  that  even  a  portion 
of  its  lipoid-globulin  has  been  destroyed. 

12. — Section  of  a  syphilitic  lymphatic  gland,  fixed  in  50  per  cent,  alcohol  and  treated 
for  twelve  houre  with  70  per  cent,  alcohol,  before  being  stained  with  pyronin  and  methyl  green. 
The  phase  shown  is  a  trophozoite,  in  a  comiective-tissue  cell.  It  will  be  noted  that  the  pyronino- 
phile properties  of  the  syphihtic  parasite  are  unimpaired,  while  those  of  the  protoplasm  of  the  plasma 
cells  and  the  nucleoli  are  faintlv  diminished. 


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Plate  22. 


CHEMISTRY   OF   THE    LEUCOCYTOZOON   SYPHILIDIS.  31 

acidophilic.  No  doubt,  in  part  this  conception  is  correct,  but  there  is  also  no 
doubt  that  it  was  carried  very  much  too  far.  After  all,  fixed  protoplasm  is  an 
amphoteric  substance,  i.e.,  it  can  act  as  a  base  or  as  an  acid  ;  for  instance,  the  proto- 
plasm of  plasma  cells  stains  well  with  acid  fuchsin,  which  is  an  acid  dye,  or  with 
pyronin,  which  is  a  basic  dye.  Although  it  stains  with  both,  it  stains  better  with  the 
latter  than  with  theformer ;  therefore,  under  ordinary  circumstances,  it  may  be  stated 
that  protoplasm,  using  the  word  in  a  very  general  sense,  prefers  to  act  as  an  acid. 

From  my  description  of  the  Lencocijtozoon  syphilidis,  and  from  the  coloured 
plates  which  illustrate  this  book,  it  will  be  seen  that,  by  using  Pappenheim's 
stain  (a  mixture  of  pyroniu  and  methyl  green),  the  syphilitic  bodies  stain  with 
pyronin  ;  but  that  they  differ  from  all  other  cells,  in  that  the  nucleus  also  apparently 
stains  with  pyronin,  and  with  a  much  deeper  red  than  the  rest  of  the  cell.  Working 
on  the  reaction  hypothesis,  or  on  the  electrolytic  theory,  one  must  assume  then,  that 
the  protoplasm,  and  especially  that  of  the  nucleus  of  the  syphilitic  organism,  is 
strongly  basophilic,  and  is  negatively  charged.  It  has,  however,  already  been 
shown  to  be  partly  acidophihc,  from  the  in  vivo  examinations,  when  it  was  pointed 
out  that  certain  phases  showed  an  affinity  for  methylene  red.  We  have,  then,  a 
paradox,  and  a  solution  to  the  problem  can  be  found  only  if  we  adopt  Unna's 
theory  of  oxidation  and  reduction. 

Methylene  violet,  like  methyl  green,  is  a  reduction-sensitive  dye,  although 
not  to  the  same  degree.  The  reason  why  certain  phases  stain  with  methylene  red, 
is  not  because  the  protoplasm  is  acidophilic,  but  because  it  has  reducing  properties  ; 
and,  as  methyl  green  is  far  more  sensitive  than  methylene  violet,  every  phase 
stains  with  pyronin,  while,  only  in  those  in  which  the  reducing  action  is  greatest,  is 
the  affinity  of  methylene  violet  for  nucleic  acid  overcome.  The  result  of  this  is,  that 
the  reducing  substance  stains  with  methylene  red.  This  reducing  sub.stance  does 
not  stain  very  readily  with  acid  dyes  in  fixed  specimens,  should  a  basic  dye  be 
present  as  well ;  because  if  pyronin  is  supplanted  by  acid  fuchsin,  most  of  the 
nuclei  of  the  syphihtic  organisms  .stain  with  methyl  green  (Plate  22  (6) ).  Therefore, 
this  characteristic  pjToninophile  .substance  of  the  syphihtic  organisms  is  a  strong 
reducing  agent,  is  basophihc,  and  ,so  is  negatively  charged,  according  to  the  electro- 
lytic theory  ;  but  the  action  of  its  electric  charge  is  overshadowed  by  its  reducing 
action.  Therefore,  we  have  another  extremely  important  factor  coming  into  play 
in  the  act  of  staining. 

Seeing  how  sensitive  a  stain  methyl  green  is,  it  at  once  appears  obvious  that 
great  caution  must  be  taken  in  choosing  the  most  suitable  fixing  reagent,  and  that 
any  fixing  reagent  which  robs  the  nucleus  of  its  oxygen  will  naturally  prevent 
staining  with  methyl  green,  and  will  also  alter  the  action  of  the  medium.     Fixing 

c 


32  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

tissue  for  24:  hours  in  a  1  per  cent,  solution  of  platinum  chloride  increases  the 
capacity  of  the  nuclei  for  methyl  green,  but  it  is  an  expensive  solution,  and  it  does 
not  give  such  good  results  as  some  other  fixing  reagents.  Mercuric  chloride  has  the 
disadvantage  that  the  sections  may  stain  unevenly,  since  it  increases  the  capacity 
for  methyl  green  staining  only  in  the  situation  where  it  remains,  and  diminishes 
it  in  those  situations  where  it  is  reduced  by  the  tissue.  If  mercuric  chloride  is 
employed  in  an  alcoholic  solution  as  a  fixing  reagent,  quite  good  sections  may  be 
obtained  with  Pappenheim's  stain,  and  the  effect  is  enhanced  if  a  little  acetic  acid 
is  added  to  the  mixture.  Chrome  salts  destroy  the  staining  properties  of  pyronin 
and  methyl  green.  Osmic  acid  alone,  or  in  conjunction  with  other  acids, 
diminishes  the  receptivity  of  protoplasm  to  most  dyes. 

Formalin,  owing  to  the  formic  acid  which  it  so  frequently  contains  as  an 
impurity,  not  only  diminishes  the  staining  properties  of  protoplasm,  but  also 
markedly  reduces  the  power  of  the  nuclei  to  stain  with  methyl  green.  Including 
other  fixing  reagents  which  are  seldom  used,  and  are  not  available  for  obtaining 
satisfactory  sections  with  Pappenheim's  stain,  practically  only  alcohol  remains. 
From  several  experiments  I  have  undertaken,  I  have  been  convinced  that  alcohol 
is  far  and  away  the  finest  fixing  reagent  we  possess  at  present,  as  it  allows  staining 
with  most  of  the  stains  in  general  use,  it  fixes  by  coagulation,  and  forms  no  chemical 
compound  with  the  cells.  Therefore  it  is  extremely  well  adapted  for  the  purpose 
of  micro-chemical  research,  when  fresh  sections  are  not  employed. 

I  employ  either  absolute  alcohol,  or  50  per  cent,  alcohol  ;  the  former  causes 
shrinking  of  the  intercellular  tissue,  but  not  so  much  shrinking  of  the  individual 
cells,  and  its  main  advantage  is  that  coagulation  is  immediate.  The  moment  the 
tissue  is  removed  from  the  body,  it  is  put  into  absolute  alcohol,  and  allowed  to 
rest  on  wool.  Whenever  alcohol  is  used,  a  pad  of  wool  should  rest  on  the  bottom 
of  the  bottle,  so  as  to  allow  the  alcohol  to  remain  approximately  the  sanje  strength 
throughout,  while  the  water  extracted  from  the  tissue  sinks  through  the  wool.  This 
simple  device  also  leads  to  a  great  saving  of  alcohol.  The  tissue  remains  for  12  hours 
in  absolute  alcohol,  and  it  can  then  be  changed  into  two  further  lots  of  absolute 
alcohol  for  12  hours  each,  or  be  put  back  to  50  per  cent,  and  gradually  taken  up,  in 
the  usual  way.  Cedar  wood  oil  is  used  for  clearing,  as  it  does  not  harden  the  tissues 
to  the  same  extent  as  xylene.  Before  the  tissues  are  put  into  wax,  two  changes  of 
xylene  are  used,  for  1-2  hours  each,  as  wax  penetrates  better  after  the  tissue  has 
been  through  xylene.     The  wax  used  is  a  mixture  of : — 

Paraffin  (melting  point  60'  ('.)...         ...         ...         8i  parts. 

Stearin       ...         ...         ...         ...         ...         ...         1  part. 

Wax  ...         ...         ...         ...         ...         ...         i  jiart. 


CHEMISTRY    OF   THE   LEUCOGYTOZOON    SYPHILIDIS.  33 

The  melting  point  of  the  prepared  article  is  53°  C,  and  the  tissue  is  left  in  three 
changes  of  this,  for  about  six  hours  altogether.  The  whole  of  the  secret  of  getting 
good  paraffin  sections,  is  to  be  absolutely  certain  that  the  tissue  is  fully  dehydrated. 

The  tissues  can  also  be  fixed  in  50  per  cent,  alcohol,  if  allowed  to  remain  in 
the  solution  for  2i  hours,  and  then  for  24  hours  each  in  70  and  90  per  cent., 
and  12  hours  each  in  three  changes  of  absolute  alcohol,  and  so  on  as  before. 
There  is  not  so  much  shrinkage  of  the  tissue,  and  most  excellent  Pappenheim- 
stained  sections  may  be  obtained. 

For  some  tests  of  minor  importance,  celloidin  sections  are  preferable,  but,  for 
general  purposes,  I  much  prefer  paraffin,  as  thinner  sections  can  be  obtained.  They 
can  be  more  easily  fixed  to  the  cover  shps,  and  one  does  not  have  to  go  through  the 
troublesome  procedure  of  removing  the  celloidin,  as  is  necessary  when  anihne  dyes 
are  being  used,  owing  to  the  intense  avidity  which  celloidin  has  for  many  of  them. 

If  Pappenheim's  stain  is  to  be  used,  I  proceed  as  follows  :  Eoughly  three 
parts  of  a  saturated  aqueous  solution  of  pyronin  are  mixed  with  one  part  of  a 
saturated  aqueous  solution  of  methyl  green,  immediately  before  use.  This  mixture 
assumes  a  red-purple  colour.  In  this  stain,  the  sections  may  be  left  from  5  minutes 
indefinitely,  as  overstaining  is  impossible.  After  being  in  the  stain,  the  sections 
are  transferred  to  a  freshly  prepared  distilled  water  solution  of  resorcinol,  which 
is  merely  used  for  washing  off  the  stain.  Here  they  are  left  for  about  a  minute, 
and  then  they  are  put  into  a  freshly  prepared  absolute  alcoholic  solution  of  resorcinol, 
and  are  kept  in  it  until  all  the  superfluous  stain  has  come  awa)^ 

These  resorcinol  solutions  are  absolutely  essential,  as  they  act  as  mordants, 
and  I  regard  mordanting  after  staining  as  superior  to  Uima's  method,  which 
consists  in  adding  carbolic  acid  to  the  stain,  so  enabling  the  stain  to  be  prepared 
and  always  to  be  ready  for  use.  The  stain  is  sold  under  the  name  carbol-pyrouiu- 
methyl  green.  The  great  disadvantage  of  the  ready  prepared  stain  is,  that  the 
pyronin  comes  out  too  cpiickly  in  the  dehydrating  process,  while,  if  resorcinol  be 
used,  this  is  not  the  case.  The  amount  of  resorcinol  crystals  used  in  the  first  watch 
glass  is  about  0" 3  grm.,  and  in  the  absolute  alcohol  watch  glass,  just  double  the 
quantity.  From  the  resorcinol,  the  sections  go  through  three  changes  of  absolute 
alcohol,  two  of  xylene,  and  are  then  mounted  in  balsam. 

As  ethyl  alcohol  may  abstract  the  pyronin  stain  from  the  sections,  such 
clearing  fluids  may  be  used  to  take  its  place  as  chloroform,  lavender  oil,  or  bergamot 
oil.     Clove  oil  should  never  be  employed,  owing  to  its  powerful  reducing  action. 

Xylene  fortunately  acts  indifferently,  but  Canada  balsam,  in  time,  owing  to 
its  reducing  and  acidic  action,  destroys  the  staining  effect.  Dammar,  dis.solved  in 
xylene,  forms  a  better  medium  for  preserving  the  section.     For  a  year  or  two,  or 

C  2 


o 


34  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT    OF   SYPHILIS. 

even  longer,  sections  stained  in  the  above  method  and  mounted  in  Canada  balsam, 
show  a  much  sharper  contrast  of  colour  ;  the  pyronin  stands  out  clearer,  the  orange 
colour  of  the  mast  cells  is  more  distinct,  but  the  methyl  green  staining  is  somewhat 
weaker,  and,  as  time  proceeds,  it  is  the  methyl  green  stain  which  first  disappears. 
Some  sections,  prepared  seven  years  ago,  are  as  good  as,  and  in  many  respects  o\ving 
to  increase  of  sharpness,  better  now  than  then. 

In  a  Pappenheim-stained  section,  the  protoplasm  of  the  groundwork  and 
connective-tissue  cells  stains  a  rose-pink,  and  has  a  finely  granular  appearance, 
whereas  the  protoplasm  of  the  plasma  cells  stains  a  clear  red  (Plate  1).  All  nuclei 
stain  green,  the  nucleoli  a  brilliant  red,  the  mast  cell  granules  orange,  and  all  bacterial 
and  protozoal  bodies  red.  The  protoplasm  of  the  syphilitic  bodies  stains  a  rose 
pink  to  red,  and  the  nuclei,  stain  a  deeper  red.  The  difference  in  the  rose-pink  to 
red  of  the  protoplasm  is  most  marked  in  the  female  cells,  and  depends  upon  whether 
they  have  been  impregnated  or  not,  as  the  fertilised  female  cells  and  zygotes  always 
stain  more  deeply.  At  first  sight,  one  might  conclude  that  the  supposed  nuclear 
part  of  the  sj-philitic  organism,  because  it  contains  no  nucleic  acid,  stains  deeply 
with  pyronin  ;  but  I  have  endeavoured  to  prove  that  such  a  surmise  is  incorrect. 

I  added  acetic  acid  to  the  alcohol  in  which  the  tis.sues  were  fixed,  in  the  propor- 
tion of  1  c.c.  glacial  acetic  acid  to  7-5  c.c.  either  absolute  or  50  per  cent,  alcohol,  with 
the  hope  that,  if  any  nucleic  acid  was  present,  the  acetic  acid  would  precipitate 
it.  When  the  sections  were  stained,  I  found  that  the  general  pyronin  staining  had 
not  been  interfered  with,  that  the  methyl  green  staining  was  strongly  intensified, 
and  that  some  of  the  nuclei  of  the  syphilitic  bodies  stained  a  brilliant  green,  which 
at  once  proved  that  they  contained  nucleic  acid  (Plate  13  (1) ).  The  addition  of  acetic 
acid  to  the  alcohol  used  for  fixing  in  ordinary  staining  with  pyronin  and  methyl  green, 
gives  better  residts  than  if  alcohol  is  used  alone,  owing  to  the  fact  that,  apart  from 
the  nucleic  acid  being  precipitated,  the  swelHng  action  of  the  acetic  aeJd  on  the 
cells  is  counterbalanced  by  the  shrinking  action  of  the  alcohol,  and  ince  versa.  For 
special  staining,  as  when  the  demonstration  of  micro-organisms  is  required,  alcohol 
alone  is  the  one  and  only  fixing  reagent. 

As  methyl  green  is  one  of  the  ingredients  of  Ehrhch's  triacid  .stain,  and  as 
the  red  dye,  acid  fuchsin,  is  an  acid  dye  in  contradistinction  to  pyronin,  which  is 
basic,  I  stained  some  sections  with  this  mixture,  with  the  result  that  the  protoplasm 
of  the  s}T)hilitic  bodies' stained  red,  while  the  nuclei  stained  green,  another  proof 
that  the  nuclei  contain  nucleic  acid  (Plate  22  (6)  ).  It  can,  therefore,  be  assumed 
that  there  is  some  substance  either  in  or  over  the  nucleus  of  the  sj'philitic  parasites 
which  is  a  strong  reducing  agent,  as  it  prevents  the  methyl  green  from  getting  at  the 
nucleus,  and  that  it  prefers  basic  to  acid  dyes. 


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Aniiuoplasnia  cells  in  fixed  tissue. 

1.  Shows  a  luultiloculatotl  aminoplasma  cell  iu  tlie  ceuti'o. 

2.  Shows  two  bilobed  amiuoplasma  cells,  one  on  each  side. 


Plate  23. 


cing  p.  r!4. 


CHEMISTRY    OF   THE    LEUCOCYTOZOON    SYPHILIDKS.  35 

My  next  step  was  to  try  to  determine  the  reducing  action  of  this  substance, 
and  also  its  degree  of  sohibihty  in  various  reagents. 

Reducing  action. — («)  Sections  were  stained  for  1-2  minutes  in  a  freshly 
prepared  1  per  cent,  solution  of  potassium  permanganate,  then  they  were  washed 
in  water,  decolourised  in  oxalic  acid  if  overstained,  dehydrated,  and  mounted  ins 
balsam.  All  protoplasm  has  a  reducing  action,  and  consequently  it  stains  browu' 
with  potassium  permanganate,  while  the  nuclei  remain  unstained.  The  protoplasm, 
of  the  syphihtic  bodies  has  a  greater  reducing  action  than  ordinary  granoplasm,. 
and  some  of  the  nuclei  stain  a  dark  brown.  If  the  section  be  counterstained  with 
methyl  green,  it  is  found  that  the  nuclei  of  the  parasitic  cells  do  not  stain  so  well 
as  those  of  the  ordinary  cells,  and  in  those  parasitic  cells  the  nuclei  of  which  stain 
least  with  methyl  green,  a  clear  halo  appears  to  surround  the  nucleus.  These  cells 
have  the  strongest  reducing  action. 

(6)  Sections  were  placed  for  5  minutes  in  a  mixture  of  equal  parts  of  a  1  per 
cent,  solution  of  ferric  chloride  and  of  a  1  per  cent,  solution  of  potassium  ferri- 
cyanide.  It  is  imperative  that  these  two  solutions  shall  be  mixed  only  immediately 
before  use,  as,  if  allowed  to  stand,  a  blue  precipitate  is  slowly  formed.  The  reducing 
action  of  the  granoplasm  converts  the  ferricyanide  into  ferrocyanide,  with  the 
result  that,  where  the  reduction  is  greatest,  a  beautiful  Berlin  blue  colour  is  formed 
in  the  presence  of  the  ferric  chloride.  Ordinary  granoplasm  has  a  weak  reducing 
action,  and  so  stains  green  ;  the  granoplasm  of  plasma  cells  and  of  the  syphilitic 
bodies  has  a  stronger  reducing  action,  and  so  stains  darker  green,  while  the  nucle 
of  the  ordinary  cells  do  not  stain,  but  some  of  the  nuclei  of  the  syphilitic  bodies  do 
stain  a  faint  Berlin  blue  colour  (Plate  22  (1) ).  Red  blood  corpuscles  also  give  the 
Berlin  blue  reaction,  and  so  do  the  aminoplasma  cells,  both  to  a  more  marked  degree 
than  the  nuclei  of  the  syphilitic  bodies.  Ordinary  nucleoli  have  likewise  a  reducing 
action  on  ferric  ferricyanide,  and  they  tend  to  stain  a  very  faint  Berlin  blue  colour. 
There  is  something  quite  characteristic  in  the  appearance  of  the  syphilitic  bodies 
stained  with  potassium  permanganate,  and  of  those  stained  with  ferric  ferricyanide, 
because  in  the  former,  when  counterstained  with  methyl  green,  the  nucleus  appears 
smaller  than  it  really  is  ;  there  is  less  nucleus  exposed  to  take  the  methyl  green. 
In  both  it  appears  to  be  irregular,  and,  scattered  here  and  there  about  the  nuclei, 
are  small  non-staining  transparent  areas. 

I  will  deviate  somewhat  from  my  course  here,  and  dwell  upon  the  aminoplasma 
cells  (Plates  20,  23). 

The  aminoplasma  cell  is  a  form  of  plasma  cell,  which  Unna  has  called,  from 
his  examinations  thereof  in  fixed  specimens,  hyaline  plasma  cell.  The  term 
"  Hyahne "  rather  suggests  some  relationship  to  cartilage,   although  it  is  very 


36  THE   BIOLOGY,    CLINICAL   ASPECT    AND   TREATMEXT   OF    SYPHILIS. 

largely  used  for  substances  of  which  the  obserYer  has  no  knowledge.  Now,  hyaline 
cartilage  is  a  strongly  basophihc  substance  owing  to  its  chondroitin-sulphuric 
acid  radicle,  and  therefore  it  possesses  great  affinity  for  basic  dyes.  Unna's 
hyaline  plasma  cells  are,  on  the  other  hand,  acidophihc,  and  they  contain  no  acid 
radicle  ;  furthermore,  they  have  very  strong  reducing  properties,  and  so  cannot 
stain  with  methyl  green,  and,  as  I  shall  show  presently  that  this  reducing  action 
is  due  to  tyrosine,  I  consider  that  the  best  name  for  them  is  aminoplasma  cells. 

The  cell  is  frequently  to  be  met  with  in  syphilitic  material,  but  it  is  also  to  be 
found  in  any  very  chronic  inflammatory  lesion,  viz.,  Rkinoscleroma  and  Ulcus 
molle  serpiginosum.  In  in  vivo  specimens,  an  aminoplasma  cell  is  apt  to  be  mistaken 
for  a  zj-gote,  owing  to  the  affinity  which  both  have  for  methylene  red.  The 
distinction  becomes  clear,  when  it  is  borne  in  mind,  that  the  former  may  vary  in 
size  from  7-14  //  or  more  in  diameter,  that  it  may  have  no  nucleus,  that  the  nucleus 
stains  homogeneously  with  meth3dene  vnolet,  that  it  may  be  situated  in  the  centre 
of  the  cell  or  at  the  periphery,  and  that  it  sometimes  possesses  the  power  of  motion, 
and  may  be  extruded,  and  finally  excluded,  from  the  cell  altogether.  In  the  amino- 
plasma cells,  dots  are  also  generally  to  be  seen,  and  masses  or  strands  may  be 
situated  anywhere  and  irregularly  scattered  about  the  cell,  but  they  have  no 
connection  with  the  nucleus,  although  they  stain  deeply  with  methylene  \nolet 
(Plate  20). 

In  fixed  specimens,  the  appearance  of  these  cells  is  very  different,  and  instead 
of  being  round,  homogeneous  cells,  they  are  often  irregular  in  shape  and  divided 
up  into  irregular  sized  loculi  or  balls  of  protoplasm,  many  of  which  become  loose 
and  scattered  about  in  the  tissue.  These  balls  stain  with  safranin,  and  acid  fuchsin, 
and  give  a  Berhn  blue  reaction  with  ferric  ferricyanide.  They  do  not  stain  well 
with  pyronin,  but,  in  some  specimens,  strands  of  protoplasm  are  to  be  noticed  in 
between  the  loculi,  and  they  do  stain  with  pyronin.  The  strands  are,  no,  doubt, 
the  same  as  the  dots,  masses,  and  strands,  which  were  described  in  the  in  vivo 
method  as  showing  an  affinity  for  methylene  violet  (Plate  23). 

These  ballooned  plasma  cells  have,  in  some  cases,  lost  their  nuclei,  whilst,  in 
other  cases,  the  nucleus  is  lengthened  out  and  fits  one  apex  of  the  cell  as  a  cap 
does  the  head,  and,  not  infrequently,  sends  string-hke  processes  down  over  the  cell 
protoplasm.  These  cells  are,  no  doubt,  degenerated  cells,  because  the  protoplasm 
gives  amino-acid  reactions,  and,  in  the  most  degenerated  cells,  the  nucleus  gives 
the  histone  reaction,  and  fails  to  stain  with  methyl  green. 

From  what  has  been  said,  it  will  at  once  be  seen  that  the  sj^hilitic  bodies  bear 
points  of  resemblance  to  the  aminoplasma  cells,  but  that  they  differ  in  the  very 
striking  point,  that  the  most  reducing  part  of  the  s'V'philitic  body  stains  deeply 


CHEMISTRY    OF  THE    LEUCOCYTOZOOX    SVPHILIDIS.  37 

with  pyroiiin,  whilst  the  most  reducing  part  of  the  aniinoplasnia  cell  stains  faintly 
with  pyrouin.  As  I  have  shown  that  the  reducing  substance  of  the  former  is 
basophilic,  it  at  once  appears  obvious  that  that  of  the  latter  is  more  acidophilic. 

The  Berhn  blue  formation  is  a  fixed  chemical  process  between  tissue  and  reagent, 
since,  although  the  colour  can  be  caused  to  vanish  with  alkalis,  it  immediately 
returns  on  the  addition  of  an  acid.  As  the  feeble  reduction  areas  are  more  quickly 
decolourised  than  the  firm  Berlin  blue  areas,  weak  alkalis  may  be  used  to  decolourise 
the  former,  and  the  protoplasm  of  the  cells  can  then  be  counterstained  with  an 
aniline  dye. 

(c)  The  third  reaction  I  tried  was  with  tetranitrochrysophanic  acid 
(Ci5H80j(NOJj).  It  is  a  crystalline  product,  obtained  from  chr3-sarobin,  which 
is  dissolved  in  acetic  acid,  and  treated  with  nitric  acid.  The  reagent  is  insoluble 
in  water,  and,  owing  to  the  reducing  power  of  ethyl  and  methyl  alcohol,  it  has  to 
be  dissolved  and  kept  in  chloroform  or  xylene. 

After  staining  for  10  minutes,  the  sections  are  returned  to  chloroform,  put 
through  three  changes,  and  through  xylene,  and  then  mounted  in  balsam.  Weak 
reducing  agents  stain  a  pale  red-rose,  strong  reducing  agents  stain  red.  The 
protoplasm  stains  pale  rose-red,  nuclei  remain  unstained,  syphilitic  bodies  stain 
a  deeper  red,  but  the  contrast  is  not  so  clear  as  in  {a)  and  (b). 

In  tissues  there  are  four  chief  classes  of  bodies  : — 

1.  Proteins.         2.  Carbohydrates.         3.  Fats. 
4.  Cholesterol,  lecithin  and  allied  lipoids. 

All  four  groups  possess  reducing  properties  in  varying  degrees,  but  the  second 
may  be  ruled  out  in  the  present  discussion,  as  will  be  shown  later.  Therefore,  the 
reducing  substance  must  be  a  protein,  a  derivate  of  a  protein,  a  fat,  or  a  lipoid. 
Speaking  generally,  pure  proteins,  fats  (olein  excepted),  and  lipoids,  are  not  strong 
reducing  agents,  but  derivates  of  proteins  are,  especially  the  amino-acids,  and 
here  is  appended  a  list  of  amino-acids,  with  their  action  on  potassium  perman- 
ganate, and  on  the  ferric  ferricyanide  mixture  (after  Unna)  : — 


Amino-acids. 

OlnO^. 

Iron  mixture 

Asparagiue 

— 

- 

-Manine... 

— 

— 

Phenylalanine 

— 

— 

Leucine 

_i_ 

-t- 

Glutaminic  acid           

-1- 

-1- 

Glycokoll 

-t-  + 

- 

Cystine 

-l-H- 

- 

TjTOsine  and  Tryptophane     ... 

+  +  + 

-i-  +  -|- 

38  THE    BIOLOGY,    CLINICAL   ASPECT    AND   TREATMENT   OF   SYPHILIS. 

The  amino-acids  which  -par  excellence  give  the  Berlin  bhie  reaction  are  tyrosine 
and  trj'ptophaue,  and,  to  prove  that  these  plasma  cells  contained  tyi'osine,  some 
sections  were  stained  in  Millon's  reagent,  with  the  result  that  the  recognised 
reaction  was  obtained.  Millon's  reaction  was,  on  the  other  hand,  not  given  by 
the  syphihtic  bodies  ;  therefore,  the  reducing  substance  of  the  syphilitic  bodies  is 
not  dependent  upon  tyrosine  for  its  action. 

So  far  as  amino-acids  are  concerned,  it  may  be  said  that  the  syphilitic  bodies 
contain  none  in  the  free  state.  Feehng  that  the  protein  molecule  existed  as  such, 
attention  was  first  directed  towards  this  substance,  and  all  Unna's  experiments, 
which  led  him  to  divide  the  proteins  into  albumoses,  were  repeated. 

{«)  Tlte  protoplasmic  portion  of  the  syphilitic  organism. 

Eecent  work  has  proved  to  me  that  Unna's  arbitrary  division  of  albumoses  is 
not  justifiable.  To  say  that  granoplasm  is  a  very  special  albmnose,  as  Unna 
ventures  to  do,  can  scarcely  be  correct,  since  the  granoplasm  of  connective-tissue 
cells  behaves  differently  froni  that  of  plasma  cells.  The  greatest  difference  is  also 
to  be  noticed  in  the  individual  plasma  cells  themselves,  depending  upon  their  stage 
of  development  and  degeneration,  and,  lastly,  the  behaviour  of  organisms  and 
protozoa  is  as  different  again,  and  all  behave  differently  according  to  the  method 
of  fixation. 

Unna  states  that  granoplasm  is  a  deuteroalbmnose,  and  not  a  primary 
albumose.  Although  it  differs  from  the  former,  owing  to  its  greater  insolubihty, 
and  in  this  respect  resembles  an  acroalbumose  which  belongs  to  the  latter  group, 
the  assumption  is  made  that  granoplasm  is  a  deutero-albimiose,  which  has  probably 
been  formed  from  an  acroalbumose.  The  opinion  is  now  generally  held  that 
albumoses  are  degeneration  products  of  protein,  and  that  the  protein  of  a  cell 
consists  of  albumin,  globidin  and  Upoid-globulin.  The  albumin  is  the  most  easily 
destroyed  by  reagents,  then  the  globulin,  and  finally  the  Hpoid-globuhn.  The 
last  is  practically  insoluble  in  most  of  the  reagents  used.  Owing  to  the  insolubility 
of  Hpoid-globuhn,  it  was  always  regarded  as  nucleo-protein,  but  later  on  it  will  be 
seen  that  such  a  conception  is  incorrect.  Unna,  and  most  other  observers,  treated 
the  sections  beforehand  with  alcohol  and  ether,  to  extract  the  lipoids,  but,  as  this 
work  will  show  that  adsorbed  hpoids  cannot  be  so  extracted,  naturally  the  inter- 
pretation of  their  conclusions  cannot  be  correct. 

To  make  this  very  complicated  part  of  the  subject  as  clear  as  possible,  it  may  be 
said  that  the  most  soluble  granoplasm  is  that  met  with  in  the  connective-tissue 
cells  and  groundwork,  then  comes  the  granoplasm  of  some  plasma  cells,  then  of 
other  plasma  cells,  then  of  the  embryonic  lymphocytes  and  nucleoli,  and  finally 


CHEMISTRY    OF  THE    LEUCOCYTOZOON   SYPHILIDI8.  39 

of  the  syphilitic  bodies.  Here  we  must  halt  for  a  moment,  as  in  the  syphilitic 
bodies  ■we  are  dealing  with  two  distinct  proteins,  one  which  stains  pink  to  red 
with  pyronin,  the  other  highly  refractile,  which  stains  deep  red  with  pjTonin. 
The  former  of  these  proteins  is  the  groundwork  or  granoplasm  of  the  cell,  and 
resembles  ordinary  granoplasm  ;  the  latter  may  cover  the  whole  cell,  or  only  the 
nucleus,  and  it  is  extremely  resistant  to  reagents,  and  therefore  does  not  resemble 
ordinary  granoplasm  ;  this  is  the  protein  which  may  be  called  the  pyroninophile 
substance. 

As  the  granoplasm  of  the  syphilitic  bodies  resembles  ordinary  granoplasm, 
the  protein  of  the  syphihtic  bodies  will  be  referred  to  as  the  pjToninophile  substance, 
since  it  is  the  chemistry  of  this  substance  that  is  to  be  imi-avelled. 

Unless  otherwise  stated,  the  following  experiments  were  undertaken  with 
sections  which  had  been  fixed  in  50  per  cent,  alcohol,  and  which  were  placed  in  the 
different  reagents  for  12  hours  at  room  temperature,  and  then  stained  with  pjTonin 
and  methyl  green. 

1.  In  distilled  water,  granoplasm  begins  to  dissolve,  the  action  is  very  much 
quicker  at  .37°,  but  the  syphihtic  bodies  remain  unaltered.  If  kept  in  water  for 
several  days,  the  avidity  for  pyronin  disappears,  and  the  nucleic  acid  is  left 
behind  to  stain  with  methyl  green.  One  may  say  that  the  protein  of  the 
syphilitic  bodies  is  insoluble  in  water.  If  normal  sahne  is  substituted  for  distilled 
water,  the  action  is  much  the  same,  and  the  syphilitic  bodies  are  still  insoluble 
(Plate  18  (4) ). 

2.  30  per  cent,  alcohol  behaves  like  normal  saline,  and  dissolves  a  greater  por- 
tion of  the  granoplasm,  but  has  no  action  on  the  syphihtic  bodies.  In  60,  70,  80, 
96  per  cent.,  and  absolute  alcohol,  the  granoplasm  remains  mostly  intact, 
depending  upon  the  concentration,  as  no  granoplasm  is  soluble  in  absolute 
alcohol.     In  no  percentage  of  alcohol  are  the  parasites  dissolved  (Plate  22  (10-12) ). 

3.  In  a  10  per  cent,  solution  of  metaphosphoric  acid,  granoplasm  and  the 
syphilitic  bodies  are  insoluble,  owing,  no  doubt,  to  the  precipitation  of  all  proteins 
by  the  acid  ;  this  is  hkewise  the  case  with  1  per  cent,  phosphomolybdic  acid,  either 
alone,  or  with  1  per  cent,  hydrochloric  acid,  1  per  cent,  phosphotungstic  acid,  picric 
acid,  and  weak  solutions  of  the  mineral  acids.  It  is  very  difficult  to  work  with  the 
above  acids,  owing  to  the  fact  that  they  all  prevent  staining  with  methyl  green, 
and  everything  stains  a  diffuse  red  with  pyronin. 

4.  Granoplasm  and  the  proteins  of  the  syphihtic  bodies  are  insoluble  in  all 
strengths  of  acetic  acid.  The  fact  that  the  nuclei  stain  green,  giving  the  first 
impression  that  the  pyroninophile  substance,  over,  or  in  them,  has  been  dissolved, 
is  only  due  to  the  marked  precipitating  action  of  acetic  acid  on  micleic  acid. 


40  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

5.  Graiioplasm  is  very  soluble  in  a  1  or  2  per  cent,  solution  of  boric  acid,  but 
is  insoluble  in  a  5  per  cent,  solution  ;  the  syphilitic  bodies,  on  the  other  hand,  retain 
their  affinity  for  pyronin.  Such  a  pretty  and  instriictive  picture  is  obtained  by 
leaving  a  section  in  1  per  cent,  boric  acid  for  12-20  hours  at  ordinary  temperature, 
and  then  staining  in  the  usual  way  with  pyronin  and  methyl  green,  that  more  than 
a  passing  mention  is  desirable.  The  grauoplasm  of  all  the  cells  has  dissolved, 
the  nucleoh  have  vanished,  those  embryo  l}anphocytes  which  stain  red,  and  ■which 
might  be  confounded  with  certain  phases  of  the  syphilitic  organism,  now  all  stain 
a  brilliant  green,  and  the  only  bodies  which  stand  out  a  brilUant  red  colour,  are  the 
syphilitic  parasites.  So,  in  this  very  simple  method,  we  have  as  fine  a  differential 
stain  as  the  Ziehl  Niellsen  for  tubercle  bacilli  (Plate  24). 

6.  In  1  per  cent,  potassium  ferrocyanide,  not  only  does  the  ordinary  grauo- 
plasm disappear,  but  the  protein  of  the  syphilitic  bodies  does  so  also,  with  the 
result  that  only  the  nuclei  stain  with  methyl  green.  If  acetic  acid  is  added  to  the 
potassium  ferrocyanide,  the  granoplasm  and  protein  of  the  syphilitic  bodies  remain 
unaltered,  and  stain  in  the  ordinary  way  (Plate  22  (2) ). 

7.  In  a  2  per  cent,  solution  of  copper  sulphate,  the  granoplasm  has  gone, 
nuclei  remain,  nucleoli  have  disappeared,  as  also  the  granoplasm  of  the  amino- 
plasma  cells ;  the  groundwork  protoplasm  of  the  .syphiUtic  female  bodies  has 
vanished,  but  the  pyroninophile  substance  over  the  nucleus  remains  intact,  and 
stains  with  pyronin,  and  most  of  the  spore  cysts  stain  red. 

8.  In  1  per  cent,  caustic  potash,  nuclei  and  all  have  dissolved. 

9.  In  mercuric  chloride  and  alcohol,  there  is  no  change. 

10.  The  syphilitic  bodies  remain  unchanged  after  treatment  with  a  1-10  per 
cent,  solution  of  lead  acetate  ;  nucleoli  are  hkewise  not  dissolved  in  this  reagent. 

From  these  experiments,  it  is  clear  that  the  pyroninophile  protein  of  the 
syphilitic  parasites  is  not  ordinary  granoplasm,  it  is  not  an  albiunin,  albumose 
or  peptone  ;  this  leaves  us  with  only  globuhn.  So,  when  the  insolubility  of  the 
protein  imder  question  is  considered,  I  think  I  am  justified  in  saying  that  it  is 
a  globulin,  or,  as  will  be  seen  later,  a  globuhn  complex.  If  the  sections  have  been 
fixed  in  absolute  alcohol,  which  prevents  the  extraction  of  salts,  and  acts  as  a  very 
powerful  coagulant,  many  of  the  above-mentioned  substances  fail  to  make  any 
alteration  ;  boric  acid,  for  instance,  is  innocuous,  and  the  syphilitic  protein  does 
not  dissolve  in  potassiurii  ferrocyanide.  To  produce  the  similar  results,  sections 
must  be  left  in  the  reagents  for  several  days  (Plate  22  (3) ). 

50  per  cent,  alcohol  can  extract  electrolytes  from  the  cells,  hence  the}'  become 
less  negatively  or  positively  charged,  and  the  charge  may  be  still  further  diminished 
by  reagents,  and,  as  electrolytes  are  essential  for  the  staining  of  fixed  specimens, 


I  Plate  21. 

Section  of  ti  syphilitic  Ijmphatic  gl:incl,  which  has  been  treated  with  a 
1  per  cent,  sokition  of  boraoic  acid,  Ijulore  being  stained  with  pyionin  and 
methyl  green.  The  section  shows  a  developing  trupliozoite  in  an  endothelial 
cell. 


Facing  p.  40. 


.1-S  axjia'l 


ban  iiino'ix<j  Aihi  b'joiide  griiaJ  O'iolad  ,I)ioii  "jioBiod  \o  iioituloa  .Jiioo  Tjq  I 
Iiiilojdloblio  an  ni  oJiosorftjo'il  gniqotovab  b  BwoJa  rioiiosB  odT     .rijfng  Iniliom 


•Ut  .i\  ^nniVi 


Plate  24. 


CHEMISTRY   OF   THE    LEUCOCYTOZOOX   SYPHILIDIS.  41 

their  complete  abstraction  will  result  in  the  absence  of  pyroniii  staining.  Hence, 
it  may  be  quite  wi-ong  to  say  that  this  or  that  protein  dissolves  in  this  or  that 
solution,  as  it  may  be  onl_y  its  electrolytes  which  are  removed  ;  therefore,  as 
previously  stated,  the  arbitrary  division  of  the  cell  proteins  into  albumoses  is  not 
justifiable. 

Absolute  alcohol  extracts  few,  if  any,  of  the  electrolytes,  hence  staining  is  not 
interfered  with.  As  the  syphilitic  protein,  when  fixed  in  50  per  cent,  alcohol, 
resists  reagents  so  remarkablj',  it  can,  from  what  has  just  been  said,  be  assumed, 
that  the  salts  or  electrolytes  are  firmly  bound  up  with  the  protein.  This  would 
not  be  the  case  unless  the  protein  was  itself  also  bound  up  in  a  highly  organised 
and  stable  complex,  so,  in  this  simple  observation  the  first  clue  is  to  be  found,  that 
the  pyroninophile  substance  of  the  syphilitic  parasite  is  a  protein  (globulin)  complex. 

(b)  The  nuclear  jmrtion  of  the  syphilitic  organism.. 

After  treatment  with  acetic  acid,  in  order  to  get  the  nuclei  of  the  syphihtic 
bodies  to  stain  with  methyl  green,  before  staining  with  pyronin  and  methyl  green, 
or  employing  Ehrlich's  triacid  mixture,  on  careful  examination,  marked  differences 
can  be  discerned  between  the  parasitic  nuclei  aiad  those  of  other  cells.  In  the 
former,  the  methyl  green  stain  gives  a  purer  green  colour,  the  stain  is  more  brilliant, 
and  it  is  evenly  distributed  throughout  the  nucleus,  or  in  other  words,  is  homo- 
geneous. If  small  lymphocytes,  or  the  nuclei  of  plasma  cells,  be  now  examined, 
and  contrasted  with  the  above,  it  will  be  noticed  that  the  green  is  darker,  and  has 
a  mixture  of  blue  or  black  ;  it  is  duller,  and  moreover,  is  distributed  into  dots  and 
strands,  which  are  the  chromatin  bodies  and  filaments.  If  attention  be  now  paid 
to  the  dividing  cells  and  the  embryo  lymphocytes,  it  will  be  noticed  that  the  green 
resembles  that  met  with  in  the  syphihtic  bodies,  and  that  the  stain  is  again  homo- 
geneous. The  only  phase  of  the  syphilitic  organism  which  at  all  resembles  in  colour 
the  lymphocytes  or  nuclei  of  the  plasma  cells  is  the  spore  cyst,  or  rather  the  sporo- 
zoites  which  the  cyst  contains.  This  very  simple  observation  is  yet  another  very 
important  argument  in  favour  of  my  view,  since  the  nuclei  of  the  developing 
syphilitic  bodies  resemble  those  of  the  developing  lymphocytes  and  the  dividing 
plasma  cells,  while  the  sporozoites  which  have  no  further  need  to  develop,  and 
are  in  the  resting  .stage,  resemble  the  mature  lymphocytes  and  resting  plasma 
cells.  Degenerated  nuclei  behave  quite  dift'erently  ;  the  division  into  chromatic 
filaments  becomes  more  marked,  the  methyl  green  first  stains  them  bluish,  then 
not  all,  and,  at  this  stage,  the  slender  chromatic  filaments  stain  red  with  the  pyronin, 
or  a  diffuse  red  stain  of  the  remaining  protein  may  result ;  therefore,  the  .syphilitic 
bodies  are  not  degenerated  nuclei. 


42  THE   BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

The  chemical  substance  of  the  nucleus  is  a  compound  of  a  protein  and  nucleic 
acid,  and  is  therefore  called  a  nucleo-protein.  This  nucleo-protein,  on  hydrolysis, 
breaks  down  into  protein  and  nuclein  ;  the  nuclein  into  protein  and  nucleic  acid  ; 
the  nucleic  acid  into  purine  bases,  viz.,  guanine,  adenine,  xanthine,  and  hypoxanthine, 
pyrimidine  bases,  viz.,  thymine,  cytosine  and  uracil,  pentoses,  and  phosphoric 
acid. 

Methyl  green  stains  only  nuclein  and  nucleic  acid,  whilst  the  protein  stains 
with  pyronin ;  therefore,  the  reason  why  degenerated  nuclei  stain  in  some  cases 
with  pyronin,  is  that  the  nucleic  acid  has  become  further  split  up,  while  the  protein 
remains  behind. 

(c)  Action  of  reagents  on  nuclei. 

A  series  of  experiments  was  next  tried,  by  leaving  sections,  which  had  been 
fixed  in  50  per  cent,  alcohol  for  20-24  hours  at  room  temperature,  in  several  reagents 
to  see  if  any  different  reactions  could  be  obtained  with  the  nucleic  acid  of  the 
syphilitic  bodies,  and  with  that  of  ordinary  cells.  The  sections  were  stained  with 
pyronin  and  meth}^  green,  and  every  experiment  which  was  undertaken  was  also 
repeated  with  sections  of  the  soft  roe  of  a  herring  {Clwpea  harengus). 

1.  Leaving  a  section  of  roe  for  20  hoiirs  in  a  concentrated  solution  of  ammonia, 
results  in  a  partial  disappearance  of  the  nucleic  acid,  but  the  cells  still  stain  with 
methyl  green,  and  they  retain  their  form.  The  chief  difference  from  the  normal 
is,  the  appearance  of  a  diffuse  mass  of  protein,  which  stains  red  with  pyronin,  and 
is,  no  doubt,  a  mixture  of  histone  and  protamine. 

In  the  sjrphilitic  section,  the  nucleo-protein  has  also  been  broken  up  ;  in  some 
nuclei,  the  nucleic  acid  has  disappeared  altogether;  in  other  nuclei,  there  are  masses 
of  it  left,  as  the  red  field  is  dotted  here  and  there  with  some  blue  masses  (methyl 
green).  The  granoplasni  of  the  cells  has  dissolved.  The  nuclei  of  the  syphilitic 
bodies  have  partly  gone,  and  the  granoplasm  has  completely  disappeared,  and 
so  also  has  the  pyroninophile  substance. 

Nucleoli  have  mostly  gone,  and  the  aminoplasma  cells  have  completely  gone. 
The  best  maintained  of  the  syphilitic  bodies  are  the  sporozoites  in  the  spore  cysts, 
and  they  still  stain  quite  intensely  with  methyl  green,  and  are,  on  the  whole,  even 
less  damaged  than  the  nuclei  in  the  herring's  roe.  Therefore,  the  sporozoites  are 
not  only  extremely  rich  in  nucleic  acid,  but  also  extraordinarily  resistant  to  chemical 
reagents. 

2.  After  leaving  sections  of  roe  in  saturated  sodium  chloride  solution,  all  the 
nucleic  acid  disappears,  and  all  that  is  seen  is  a  diffuse  mass  of  histone,  which 
stains  well  with  pyronin. 


CHEMISTRY   OF   THE    LEUCOCYTOZOOX    SYPHILIDIS.  43 

111  the  syphilitic  sections,  the  gianoplasm  of  the  cells  is  well  preserved  ;  if 
anything,  the  pyi-oniu  staining  of  the  protoplasm  of  the  plasma  cells  is  increased. 
The  nuclei,  on  the  other  hand,  are  very  much  altered  ;  they  stain  homogeneously 
a  slate  grey  colour  ;  the  chromatin  bodies  and  filaments  are  not  to  be  seen,  but 
the  nucleic  acid  is  less  disturbed  than  in  the  fishes'  roe.  The  nucleus  of  the  syphilitic 
parasite  does  not  stain  with  methyl  green,  not  because  the  nucleic  acid  is  dissolved, 
but  because  the  brilMant  refractile  pyi-oninophile  substance  has  been  precipitated, 
and  therefore  has  had  its  properties  intensified. 

The  nucleoli  are  well  preserved,  and  the  aminoplasma  cells  are  intact. 

3.  A  section  of  roe  which  has  been  treated  with  a  1  in  3  solution  of  magnesium 
sulphate  has  lost  all  its  nucleic  acid,  no  cell  outhne  is  even  discernible,  and  all 
that  remains  is  the  precipitated  histone,  which  stains  especially  brilhantly  with 
pjTonin. 

In  the  syphilitic  sections,  the  granoplasm  has  partly  dissolved,  the  nuclei 
stand  out  ;  they  stain  a  brilliant  green,  and  are  intensely  refractile,  looking  like 
pieces  of  green  glass.  The  great  difi'erence  between  the  nuclei  found  in  the  roe 
and  in  the  syphihtic  section,  can  possibly  be  explained  by  the  fact  that,  in  the 
latter,  the  nucleic  acid  has  not  been  extracted  before  the  precipitation  of  the  histone, 
with  the  result  that  the  nucleo-protein  is  maintained,  as  is  the  case  in  sections 
which  have  remained  in  potassiiun  ferrocyanide.  All  nucleoli  have  vanished. 
The  nuclei  of  the  syphilitic  phases  stain  a  brilliant  green,  and  are  much  better 
preserved  than  the  nuclei  of  other  cells  ;  all  the  pyroninophile  substance  has 
completely  disappeared. 

4.  The  only  diSerence  noticed  in  a  section  of  roe  which  has  been  in  a  0"1  per 
cent,  solution  of  calcium  chloride,  is  that  a  trace  of  histone  has  been  abstracted 
from  the  nuclei. 

In  the  syphilitic  sections,  the  staining  is  not  quite  as  good  as  it  is  under 
ordinary  circumstances.  The  pyroninophile  substance  is  not  destroyed,  but  the 
sporoblasts  and  sporozoites  show  a  greater  affinity  for  methyl  green  than  usual  ; 
therefore,  a  trace  of  the  body  is  soluble  in  calcium  chloride.  These  sections  show 
up  some  points  which  I  have  frequently  observed  in  other  sections,  and  which 
have  more  than  once  raised  the  question  as  to  whether  I  was  dealing  with  spore 
cysts,  or  with  the  degenerated  nuclei  of  pla.sma  cells. 

In  some  spore  cysts,  which  stain  with  methyl  green,  bright  red  bodies  are  to 
be  seen,  resembling  nucleoh.  There  may  be  one  or  more,  varying  in  size,  and 
frequently  the  largest  red  mass  lies  on,  and  looks  as  if  it  was  part  of,  the  biggest 
spore  body.  In  this  latter  observation  lies  the  solution.  This  large  spore  body 
is  a  part  of  a  sporoblast  which  has  to  divide  still  further  to  form  sporozoites.  and. 


44  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

as  mentioned  above,  the  oldest  sporozoites  have  generally  lost  their  pyroniiiophile 
constituent,  which  would  not  be  the  case  with  undeveloped  sporozoites.  The 
pyroniiiophile  substance  is,  no  doubt,  separated  off,  and  breaks  up  into  fragments 
in  the  groundwork  of  the  spore  cyst. 

When  the  nucleus  of  a  plasma  cell  degenerates,  it  does  not  break  up  into  a 
mass  of  circular  bodies,  but  into  a  ring  of  bodies,  some  of  which  are  circular  and 
others  oval ;  and  there  is  nothing  in  the  centre  except  a  few  strands  which  stain 
red  with  pp'onin. 

5.  In  2"5  per  cent,  sodium  chloride,  all  sections  show  the  points  brought  out 
by  the  preceding  reagent,  but  in  a  slightly  more  pronounced  degi-ee. 

6.  20  per  cent,  ammonimii  sulphate  solution  has  the  effect  of  so  breaking  clown 
the  nucleo-jjrotein  of  the  nuclei  found  in  a  section  of  roe,  that  no  di.stinct  nuclei 
are  seen,  but  only  a  diffuse  red  purple  colouration  of  the  nucleic  acid  is  left,  upon 
a  deeply  red  diffuse  groundwork  of  histone. 

In  sj'philitic  sections,  destruction  is  not  nearly  so  marked,  so  far  as  the  toute 
ensemble  is  concerned  ;  the  p}Tonin  stain  seems  to  have  been  increased,  probably 
owing  to  some  abstraction  of  histone  from  the  nuclei,  as  the  staining  capacity  of 
the  nuclei  is  very  much  weakened.     The  pyroninophile  substance  is  maintained. 

If  specimens  fixed  with  absolute  alcohol  are  used,  quite  different  results 
are  again  obtained.  Nuclei  are  not  affected  by  concentrated  ammonia,  but  the 
pyroninophile  substance  dissolves.  In  20  per  cent.  NaCl,  imcleo-protein  has  been 
spUt  up,  and  part  of  the  nucleic  acid  has  been  dissolved,  but  the  pyroninophile 
substance  is  unaltered.  If  the  syphilitic  bodies  are  closely  examined,  a  clear  white 
halo  surrounds  the  nucleus,  and  tiny  areas  of  white  are  to  be  seen  in  the  nucleus. 
The  refractility  of  the  protoplasm  of  the  plasma  cells  is  markedly  diminished,  while 
that  of  the  syphilitic  bodies  appears  to  be  increased,  which  has  the  effect  of  strongly 
differentiating  them  from  the  other  cells.  ■^ 

7.  In  0'6  per  cent,  lithium  carbonate,  the  granoplasm  of  cells  has  mostly 
disappeared,  the  nuclei  stain  homogeneouslj',  a  bluish  colour  ;  nucleoli  are  well 
maintained,  and  the  syphilitic  bodies  remain  practically  unaltered.  So  here  again 
is  a  fine  differential  method. 

((?)  Action  of  sera  on  cells. 

I  thought  it  possible  that  something  might  be  learnt  by  treating  sections  with 
different  sera,  so  the  following  experiments  were  undertaken. 

Several  cubic  centimetres  of  blood  were  withdrawn  from  a  non-s\^hilitic,  a 
case  of  early  generalised  syphilis,  and  a  case  of  late  recurrent  sj^hilis.  CTreat  care 
was  taken  to  have  the  sera  absolutely  free  from  haemoglobin,  and  when  put  into 


CHEMISTRY  OF  THE  LECCOCYTOZOON  SYPHIUDIS.  45 

the  vratch  glass,  a  covering  of  pure  toluene  was  used  to  prevent  any  bacterial  action. 
Unless  the  latter  precaution  be  taken,  bacteria  multiply  in  the  sera,  and  exert  a 
pronounced  hydrolytic  action  on  the  sections,  so  that,  even  after  20  hours,  the 
individual  cells  are  only  just  discernible.  All  sera  have  the  same  action  as  normal 
saline.  If  specimens  fixed  with  absolute  alcohol  are  treated  in  the  same  way,  there 
is  no  change,  and  in  neither  case  can  any  difference  be  detected  between  the  action 
of  the  three  sera  (Plate  22  (9) ). 

Whether  the  pyroninophile  protein  of  the  syphilitic  bodies  is  part  and  parcel 
of  the  nucleus,  or  is  only  its  sheath,  is  at  first  sight  difficult  to  ascertain.  I  inchne 
to  the  latter  view,  for  the  following  reasons. 

Morphologically,  it  looks  more  like  a  cover,  this  being  especially  noticeable 
in  potassium  permanganate  specimens  which  have  been  counterstained  with  methyl 
green,  as  the  nucleus  stains  faintly,  and  appears  hazy,  and  gives  exactly  the 
impression  of  being  covered  with  a  veil.  It  is  soluble  in  potassium  ferrocyanide, 
and,  when  sections  are  left  for  12  hoiu's  in  a  1  per  cent,  solution,  the  nuclei  stain 
better  than  ever,  and  appear  clearer  with  methyl  gi'een,  which  would  scarcely  be 
the  case  if  it  were  part  of  the  nucleus.  Moreover,  it  gives  a  faint  Berlin  blue 
reaction,  and  no  nucleus  is  known  to  do  this.  Further,  by  staining  with  dextrose- 
borax-methj'leue  blue,  during  impregnation,  there  appears  to  be  a  marked  differen- 
tiation of  ecto-  and  endoplasm,  and  even  the  spirochaetae  are  swollen.  If  it  is  not 
part  of  the  nucleus,  in  what  combination  with  protein  does  the  nuclein  and  nucleic 
acid  of  the  sj^philitic  bodies  exist  ?  That  a  protein  does  exist  is  quite  clear,  since 
the  nuclei  of  the  syphilitic  parasites  can  be  made  to  stain  with  acid  dyes,  viz., 
diazine  green,  which  mixes  very  well  with  p}Tonin  ;  and  moreover,  this  protein 
will  stain  well  with  pjTonin  when  the  nucleic  acid  has  been  separated  off,  and  then 
this  protein  is  found  to  behave  like  ordinary  granoplasm.  In  this  respect,  the 
protein  radicle  of  the  syphilitic  nucleo-protein  does  not  differ  from  that  of  ordinary 
cells. 

The  protein  of  nucleo-jjrotein  is  always  regarded  as  quite  a  .special  protein,  and 
is  said  to  possess  strong  basic  properties,  and  to  be  extremely  rich  in  hexone  bases, 
viz.,  lysine,  arginine  and  histidine. 

Nucleo-protein  is  a  complex  in  which  the  properties  of  the  protein  can  be  very 
materially  altered  by  the  pro.sthetic  group,  since  we  are  by  no  means  aware  what 
all  the  other  constituents  are,  and  therefore  we  cannot  tell  when  they  have  been 
removed  ;  we  can  never  be  sure  that  we  are  dealing  with  the  protein  only. 

It  has  already  been  shown  that  the  division  of  the  proteins  of  the  cell  proto- 
plasm is  purely  arbitrary,  and  the  separation  of  the  nucleo-proteins  is  likewise  no 
doubt  artificial,  since,  when  the  protein  of  the  nucleo-protein  is  separated  out,  it  gives 


46  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

the  same  micro-chemical  tests,  and  behaves  in  the  same  way  to  stains,  as  does  the 
cell  granoplasm.  Therefore,  the  syphilitic  nucleus  does  not  differ  in  gross  details, 
from  the  nuclei  of  its  host's  cells. 

For  lysine  and  arginine  I  have  as  3'et  been  unable  to  fijid  a  specific  micro- 
chemical  test,  as  immersing  sections  first  in  a  freshly  prepared  solution  of  diazo- 
benzene-sulphonic  acid,  and  then  washing  with  a  1  per  cent,  solution  of  NaOH, 
did  not  give  the  characteristic  pink  colour  which  is  seen  in  the  micro-chemical  test 
for  arginine.  Keversing  the  solutions  by  using  the  alkali  fii-st  made  no  difference. 
Whichever  method  was  employed,  a  beautiful  stable  orange  colour,  which  stained 
both  the  protoplasm  and  the  nuclei,  resulted. 

The  well-known  test  for  histidine,  namely,  bromine  water  and  acetic  acid, 
also  gave  negative  results,  both  before  and  after  hydrolysing  with  a  0"5  per  cent, 
solution  of  hydrochloric  acid.  Oddly  enough,  a  section  which  had  been  treated 
with  bromine  water  and  acetic  acid  quite  failed  to  give  the  orange  colour  with 
diazobenzene-sulphonic  acid  and  sodium  hydroxide,  which  looks  as  if  either  the 
histone  or  the  hexone  bases  had  formed  a  halogen  compound,  as  of  course  they 
are  well  known  to  do,  and  the  bromo-histidine  compound,  for  instance,  does  not 
give  the  characteristic  reactions  of  the  base. 

Failing  to  get  the  typical  hexone  reactions,  I  did  not  expect,  nor  did  I  succeed 
in  getting,  a  positive  imidazole  reaction  by  treating  sections  with  ammonia  and 
silver  nitrate.  I  also  tried,  but  once  more  without  success,  to  get  a  positive  biuret 
reaction  which  is  obtained  with  histone  ;  the  failure  was  due  to  the  destruction 
of  the  tissues  by  the  strong  soda  solution,  which  is  imfortunately  necessary  for 
the  reaction. 

All  nuclei  are  stated  to  contain  phosphorus,  which  is  intimately  bound  up 
with  the  nucleic  acid  radicle  of  the  nucleo-protein,  and  which  disappears  when  the 
nucleic  acid  is  hydrolysed  ;  and,  as  it  is  the  nucleic  acid  radicle  which  shows  the 
affinity  for  methyl  green,  it  is  possible  that  this  acid  plays  a  part  in  the  selective 
action  of  nuclei  for  methyl  green.  The  nuclei  of  the  syphilitic  parasites,  when 
the  pyroninophile  membrane  covering  them  is  removed  or  prevented  from  staining, 
stain  not  only  brilliantly  with  methyl  green,  but  also  show  a  greater  resistance 
to  hydrolytic  agents  than  do  the  nuclei  of  ordinary  cells  ;  hence  it  might  be 
expected  that  the  parasitic  nuclei  were  especially  rich  in  phosphorus. 

To  see  whether  this  surmise  was  correct,  the  following  experiments  were  under- 
taken : — 

Phosphorus. — Both  fresh  sections,  and  specimens  fixed  with  absolute  alcohol, 
the  latter  giving  quite  as  good  results  as  the  former,  were  placed  in  a  mixture  of 
molybdic  acid,  ammonia  and  nitric  acid,  and  kept  therein  at  37°  for  from  10  minutes 


CHEMISTRY    OF   THE    LEUCOCYTOZOON    SYPHILIDIS.  47 

to  48  hours.  One  is  supposed  to  regard  as  inorganic  phosphorus  that  which  makes 
its  appearance  in  the  first  10  minutes,  but  when  sections  are  examined  so  early 
only  negative  results  are  obtained.  After  24  hours,  good  staining  effects  can  be 
obtained,  but  the  staining  is  sharper  if  the  sections  are  left  in  the  mixture  for  even 
another  day. 

The  sections  are  washed  well  in  distilled  water,  and  are  then  placed  in  a  2  per 
cent,  solution  of  phenylhydrazine  hydrochloride,  taken  direct  through  alcohol, 
and  mounted  in  balsam. 

The  presence  of  phosphorus  is  indicated  by  a  green  colour-,  and,  when  the 
sections  are  examined,  it  is  found  that  both  the  protoplasm  and  the  nuclei  of. 
nearlj^  all  cells  are  stained.  The  staining  is  deepest  in  the  syphilitic  bodies,  and 
then  in  the  plasma  cells  ;  there  appears  to  be  no  great  difference  in  the  staining 
properties  of  the  nucleus  compared  with  the  cell  protoplasm,  a  fact  which  indicates 
that  the  phosphorus  in  a  cell  is  not  restricted  to  the  nucleus. 

As  nuclei  also  contain  iron  the  following  tests  were  undertaken  : 

Iron. — A.  Inorganic. 
B.  Organic. 

(A)  Inorganic. — Specimens  fixed  with  absolute  alcohol  were,  after  removal 
of  wax,  transferred  direct  from  absolute  alcohol  into  a  freshly  prepared  solution 
of  equal  parts  of  0'5  per  cent,  hydrochloric  acid  and  1  per  cent,  potassium  ferro- 
cyanide,  and  were  allowed  to  remain  therein  for  one  hour.  By  this  means  the 
cells  did  not  give  the  Berlin  blue  reaction,  nor  did  they  even  stain  green. 

Instead  of  the  hydrochloric  acid  potassium  ferrocyanide mixture,  a  0'5  per  cent, 
haematoxylin  solution  was  employed,  which  also  failed  to  prove  the  presence  of 
inorganic  iron. 

(B)  Organic. — Sections,  prepared  as  above,  were  placed  in  a  mixture  of 
sulphuric  acid  (4  vols.)  and  absolute  alcohol  (100  vols.),  and  were  left  therein  at 
37°  for  24-48  hours. 

After  24  hours,  the  sections  were  washed  in  absolute  alcohol,  and  some  were 
transferred  for  half  an  hour  into  the  hydrochloric  acid  potassium  ferrocyanide 
mixture,  whilst  others  were  stained  in  0 '  5  per  cent,  aqueous  solution  of  haematoxyhn. 
From  both  solutions  the  sections  were  taken  through  alcohol,  etc.,  and  mounted 
in  balsam.  When  the  former  were  examined,  it  was  seen  that  the  jjrotoplasm 
of  the  cells  remained  unstained,  while  the  nuclei  stained  green,  the  arrangement 
of  the  chromatin  remaining  unaltered.  Other  nuclei  stained  a  light  Berhn  blue, 
and  the  colour  was  homogeneous.  Examined  for  action  on  polarised  light,  they 
were  found  to  react  sHghtly,  while  none  of  the  other  cells  showed  a  trace  of  reaction. 

D 


48  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

These  cells  were  no  doubt  the  syphilitic  parasites  ;  the  nuclei  of  which  contained 
more  organic  iron  than  those  of  the  leucocytes  and  connective-tissue  cells.  This 
suggests  the  adsorption  capacity  of  syphilitic  bodies  towards  stains. 

The  same  difiereuce  in  degree  of  staining  was  also  noticeable  in  the  haematoxylin 
specimens. 

Summary. — The  protoplasm  of  the  syphilitic  bodies  is  strongly  jjyroninophile, 
which  proves  it  to  possess  reducing  properties.  The  reducing  action  is  not  so 
strong  as  that  of  the  aminoplasma  cells,  and  therefore  it  is  not  due  to  an 
amino-acid  ;  and,  moreover,  it  prefers  basic  to  acid  dyes  which  still  further 
distinguishes  it. 

The  protoplasm  is  very  resistant  to  reagents,  and  in  all  respects  resembles 
a  globulin.  The  nucleus,  in  its  behaviour  to  d_yes  and  reagents,  mo.st  closely 
simulates  the  nuclei  of  dividing  cells. 

Hence,  neither  can  the  syphilitic  bodies  be  taken  for  cell  degenerations  nor  for 
nuclear  degenerations. 

Further  Points  concerning  the  Eeducting  Action  of  Cells,  with  Special 
Eeference  to  their  Physical  Characters. 

None  of  the  proteins  that  have  been  mentioned  have  sufficient  reducing  power 
to  form  Berlin  blue  from  the  ferric  ferricyanide  reagent  ;  therefore,  the  reducing 
action  of  some  of  the  syphihtic  bodies,  red  blood  corpuscles,  etc.,  must  be  due  to  a 
carbohydrate,  a  fat  or  a  lipoid. 

Carbohijdrates. — My  endeavours  to  find  a  carbohj'drate  in  the  syphilitic  bodies 
failed,  and  the  tests  used  are  only  of  interest  from  the  negative  information  which 
they  give. 

Keeping  sections  for  some  time  in  a  hot  solution  of  Fehhug's  reagent,  gave 
no  yellow  precipitate.  Leaving  sections  for  48  hours  at  37°  in  a  solution  of  0"5  per 
cent,  potassium  hydi-oxide  in  90  per  cent,  alcohol,  and  then  immersing  them  in 
a  2  ■  5  per  cent,  solution  of  dimethylparaminobenzaldehyde  in  1  per  cent.  HCl,  gave 
no  carmine  reaction,  which  indicates  the  absence  of  glucosamine. 

Treating  sections  with  a  15  per  cent,  alcoholic  solution  of  a-naphthol,  and 
then  examining  them  in  sulphuric  acid  for  the  furfurol  reaction,  owing  to  the 
destruction  of  the  tissue,  gave  no  information. 

The  principal  organic  tests  and  group  reactions  either  necessitate  the  use  of 
strong  acids  or  alkalis  ;  with  the  former,  the  tissue  is,  as  often  as  not,  dissolved 
in  toto  ;  with  the  latter,  it  is  almost  certain  to  leave  the  cover  shp,  to  swell,  and 
to  become  practically  unmanageable.     Ammonia  is  the  least  offender  in  this  way, 


CHEMISTRY   OF   THE    LEUCOCYTOZOON    SYPHILIDIS.  49 

but  luifortimately  it  cannot  as  a  rule  take  the  place  of  the  potassium  and  sodium 
hydroxides. 

I  tried  also  leaving  fresh  and  fixed  sections  in  a  saturated  solution  of  copper 
acetate  at  40°  for  24  hours,  and  then  washing  them  in  a  strong  solution  of  sodium 
carbonate.  A  general  reduction  of  the  copper  occurred  in  the  fresh  sections,  but 
the  individual  cells  could  not  be  studied.  In  the  fixed  films,  the  only  cells  which 
reduced  were  those  of  the  rete  malpighii.  Therefore,  although  it  can  be  said  that 
the  tissue  cells  do  contain  sugar,  they  cannot  be  differentiated  individually. 

Resort  was  then  had  to  a  physical  test. 

By  the  use  of  Nicol's  prisms,  it  is  seen  that  the  syphilitic  cells,  when  properly 
focussed,  appear  as  bright  stars  against  a  black  background.  The  phenomenon 
is  better  marked  in  specimens  fixed  with  absolute  alcohol  than  when  50  per  cent, 
alcohol  has  been  used  for  the  same  purpose,  and  can  be  beautifully  demonstrated 
in  sections  stained  with  p}T:onin  and  methyl  green.  It  is  most  marked  over  the 
nuclear  area,  is  greater  in  zygotes  than  in  female  gametocytes,  is  very  well  marked 
in  the  trophozoite  and  male  gametocyte,  and  much  less  evident  in  sporoblasts  and 
sporozoites.  In  short,  it  is  greatest  where  the  pyronin  staining  is  deepest ;  there- 
fore, it  is  the  pyi'oniuophile  substance  that  is  concerned.  The  only  cell  constituents 
which  exhibit  this  property  are  cholesterol,  sugar,  and  b'poids. 

Cholesterol  gives  a  crystalline,  and  not  a  star-like  appearance,  as  seen  in  the 
syphilitic  parasites,  and,  moreover,  cholesterol  is  not  increased  in  the  serum  of 
syphilitic  patients.  Sugar  may  be  excluded,  because,  if  it  were  present  in  sufficient 
quantities  to  show  the  phenomenon,  it  would  give  the  micro-chemical  tests  ;  more- 
over sugar  is  soluble  in  water,  and  the  pyroninophile  substance  is  not.  Further, 
the  active  substance  of  the  parasitic  cells  must  therefore  be  lecithin,  or  rather,  its 
fatty  acid  constituent.  To  bring  still  greater  evidence  to  bear  on  this  assumption, 
I  compared  the  colloidal  particles,  in  a  case  of  pseudo-chylous  fluid  with  dextrose, 
and  in  a  case  without  dextrose,  with  the  result,  that  the  former  were  more  active 
than  the  latter,  the  activity  of  which  latter  was  comparable  in  degree  with  that 
of  the  syphilitic  cells.  The  pseudo-chylous  fluid  with  dextrose  gave  a  marked 
Berhn  blue  reaction,  which  was  not  the  case  with  the  other.  The  fluid  con- 
taining no  dextrose  had  a  reducing  action  equal  to  that  of  the  syphilitic  cells  ; 
therefore  it  appears  justifiable  to  state  that  the  syphilitic  bodies  contain  no 
dextrose. 

If  sections  be  left  for  hours,  and  even  for  days,  in  ether,  absolute  alcohol,  and 
absolute  alcohol  and  ether  mixed,  the  cells  still  retain  this  property,  and  therefore 
the  lecithin  cannot  exist  alone.  The  pyroninophile  substance  contains  protein, 
and  as  a  lecithin- protein  complex  is  known  to  exist,  and  as  the  protein  is  a  globulin, 

d2 


50  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

as  the  pyroninophile  substance  has  also  been  shown  to  be,  it  may  be  assumed 
that  this  substance  is  lecithin-globulin,  or  better  lipoid-globulin. 

Fatty  acids. — Now  what  evidence  is  there  for  assuming  that  it  contains  a  fatty 
acid  ?  I  stained  sections  with  iodine  and  with  Nile  blue  sulphate,  according  to 
the  method  of  Lorrain  Smith.  The  syphilitic  bodies  stained  with  iodine,  and  also 
very  deeply  with  a  saturated  solution  of  Nile  blue  sulphate.  Red  blood  corpuscles 
also  stained  with  iodine,  and  all  nuclei  and  nucleoli  stained  with  Nile  blue  sulphate. 
The  only  granoplasm  that  stained  with  Nile  blue  sulphate  was  that  of  the  syphihtic 
bodies,  and  of  some  of  the  plasma  cells.  The  inclusion  of  a  fatty  acid  in  the  lecithin- 
globulin  complex  is  still  further  supported  by  the  invariable  occurrence  of  a 
saturated  fatty  acid  (stearic  acid)  in  the  lecithin-globuUn  complex  of  pseudo-chylous 
fluids,  and  the  visibility  of  the  fluid  between  crossed  Nicol  prisms  is  due  to  the  fatty 
acid,  and  not  to  the  lecithin  itself. 

The  reducing  action  of  red  blood  corpuscles,  syphilitic  bodies,  protoplasm 
of  some  plasma  cells,  and  nucleoli,  is  in  all  probabihty  due  to  the  lecithin-globuhn 
complex,  and  the  change  which  takes  place  in  impregnated  female  cells  is  an  increase 
of  this  body,  which,  owing  to  its  reducing  action,  prevents  the  cell  from  staining 
with  methyl  green,  and,  owing  to  its  acid  action,  prevents  the  cell  from  showing 
a  marked  affinity  for  negatively  charged  dyes,  as  carbol  fuchsin,  etc.  Since  the 
complex  is  not  so  marked  in  unimpregnated  female  cells,  and  since  the  protein  is 
less  acid,  it  will  stain  with  carbol  fuchsin,  in  the  carbol  fuchsin-carbol  iodine  green 
method.  Owing  to  the  staining  reactions,  the  fatty  acid  must  be  a  saturated 
one,  and  as  neither  the  sj'philitic  bodies  nor  the  colloidal  particles  of  pseudo- 
chylous fluid  stain  with  osmic  acid  or  Sudan  III,  the  fatty  acid  is  clearly  not 
oleic  acid. 

As  the  syphilitic  parasite  was  shown  to  contain  lecithin,  I  thought  it  necessary 
to  repeat  the  more  important  work  which  had  been  done  in  connection  with  the 
lecithin  in  nerve  tissue,  so  the  following  tests  were  carried  out. 

1.  The  tissue  was  fixed  in  Miiller's  fluid  for  10  days,  was  frozen,  and  sections 

were  cut.     The  sections  were  transferred  to  1  per  cent,  osmic   acid  for  24  hours 

at  37°,  and  were  then  placed  in  the  following  mixture  : — 

PjTogallic  iicid  ...         ...         ...         ...         ...         15  parts. 

Sod.  sulpliite  ...         ...         ...         ...         ...  125     „ 

Sod.  nitrate  70     ,, 

Water       ...  300     „ 

and  differentiated  in  O'l  f)er  cent,  potassium  permanganate,  which  reoxidises  the 
osmiimi  which  has  not  combined.  The  bro^^l  colour  of  the  permanganate  can  be 
removed,  if  desired,  with  1  per  cent,  oxalic  acid. 


CHEMISTRY    OF   THE    LEUCOCYTOZOON    SYPHILIUIS.  51 

Considering  how  insoluble  the  syphilitic  lecithin  appeared  to  be  in  alcohol 
I  tried  alcohol  fixed  specimens  and  paraffin  sections,  but  instead  of  floating  the 
cut  sections  out  on  to  warm  water,  I  employed  a  hot  7  per  cent,  solution  of  potassium 
dichromate,  and  obtained  quite  as  good  results.  The  S3'philitic  bodies  had  a  greater 
reducing  action  upon  the  osmium  than  other  cells  had,  and  stained  a  deep  oUve 
green,  the  oidy  other  structures  which  resembled  them  were  nucleoli  and  the  amino- 
plasma  cells. 

2.  Tissues  were  fixed  for  four  days  in  10  per  cent,  formalin,  and  were  then 
placed  for  the  same  length  of  time  in  Weigert's  chrome  alum  copper  acetate  mixture, 
in  the  incubator  at  37°.  Some  sections  were  cut  in  the  frozen  state,  others  taken 
through  paraffin.  The  cut  sections  were  put  into  sulphuric  acid  alcohol  (1:500 
H2SO4  in  50  per  cent,  alcohol),  and  then  stained  for  10  minutes  in  1  per  cent,  osmic 
acid  ;  they  were  then  well  washed,  and  treated  with  5  per  cent,  pyrogallic  acid 
solution,  differentiated  in  O'l  per  cent,  potassium  permanganate,  taken  through 
sulphm'ous  acid,  and  the  fresh  sections  were  mounted  in  liquid  paraffin.  The 
paraffin  sections  went  through  the  usual  stages  to  balsam.  The  results  tallied 
with  those  obtained  from  No.  1. 

3.  Alcohol  fixed  specimens,  the  paraffin  sections  of  which  had  been  floated 
out  on  to  potassium  dichromate,  were  stained  for  24  hours,  at  room  temperature, 
in  Weigert's  haematoxyhn. 

The  syphiHtic  bodies  stain  intensely,  and  in  this  respect  they  resemble  the 
nucleoh.     The  chromatin  of  nuclei  also  stains  well,  but  the  colour  is  not  so  fast. 

4.  Paraffin  sections  of  tissue  which  had  been  floated  out  on  potassium  di- 
chromate, were  stained  for  24  hours  at  37°  in  Kultschitzky's  haematoxyUn,  were 
washed  and  decolourised  in  a  0'25  per  cent,  solution  of  sodimn  carbonate,  until 
the  sections  retained  a  light  blue  colour.  The  sections  were  then  washed,  transferred 
to  a  O'l  per  cent,  solution  of  potassium  permanganate,  then  to  sulphurous  acid, 
washed  in  a  O'l  per  cent,  solution  of  lithium  carbonate,  taken  through  alcohol, 
and  mounted  in  balsam. 

The  sections  gave  the  same  residts  as  were  obtained  from  method  No.  3. 

All  sections  were  compared  with,  and  controlled  by,  sections  from  a  case  of 
neurofibromatosis,  with  the  result  that  the  reducing  action  of  the  syphilitic  bodies 
was  practically  equal  to  that  of  the  medullated  nerve  fibres,  and  the  capacity  for 
staining  with  haematoxylin  resembled  that  of  the  axis  cylinders,  the  deep  colour 
of  which  is  no  doubt  due  to  the  presence  of  a  lipoid-protein  complex.  Recently  I 
have  studied  the  chemistry  of  Nissl's  granules,  on  the  same  fines,  and  I  find  that 
they  consist  of  lipoid-globuUn  and  not  nucleo-protein,  as  they  are  generally  held 
to  do. 


52  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT    OF   SYPHILIS. 

Summary. — The  reducing  action  of  the  pyroninophile  substance  of  the  syphilitic 
bodies  is  not  due  to  cholesterol  or  to  a  carbohydrate.  Although  it  is  active  optically, 
it  is  not  so  markedly  so  as  the  two  substances  just  mentioned. 

The  activity  is  due  to  a  fatty  acid,  and  resembles  that  of  the  particles  met 
with  in  the  fluid  from  a  case  of  pseudo-chylous  ascites.  The  particles  of  such  a 
fluid  consist  of  lecithin-globulin  with  a  saturated  fatty  acid  (stearic  acid)  in  its 
radicle.  This  physical  phenomenon  is  a  most  useful  means  of  picking  out  the 
syphilitic  bodies  in  a  section. 

Physical  and  Chemical  Properties  of  the  Lecithin-Globulin  Complex. 

The  lecithin-globuhu  complex,  when  in  solution,  gives  rise  to  a  definite 
opalescence,  and  exists  as  a  colloidal  suspension  which  can  be  removed  by  filtration 
through  a  Chamberland  candle.  It  appears  microscopically  in  the  form  of  very 
fine  refractile  granules,  which  do  not  stain  with  osmic  acid,  or  with  Sudan  III. 
These  fine  granules,  no  doubt,  owe  their  refractihty  to  the  associated  lipoid  lecithin. 
The  particles  exist  in  an  alkaline  medium,  and  possess  a  negative  charge  ;  and, 
in  consequence,  we  find  that  the  lecithin-globulin  complex  is  readily  precipitated  by 
kations,  particularly  by  the  divalent  kations,  Mg,  Ba,  and  Ca. 

The  lecithin-globulin  compound  is  readily  precipitated  by  acetic  acid,  even  in 
the  cold,  also  by  alcohol ;  half  saturation  or  full  saturation  with  ammonium  sulphate, 
and  removal  of  the  salts  b}'  dialyisis,  results  in  separation  of  the  lecithin-globulin 
complex.  Treatment  of  the  complex  with  ether  has  no  effect,  and  previous  addition 
of  alkali,  such  as  caustic  potash,  does  not  appreciably  alter  the  solubility  of  this 
body.  In  all  respects,  this  lecithin-globulin  behaves  exactly  like  the  pseudo- 
globulin  fraction  isolated  from  serum.  One  third  saturation  with  (XH4)2S04 
precipitates  the  euglobulin  fraction  from  serum,  and  this  fraction  is  soluble  in  a 
0'6  per  cent,  solution  of  sodiiun  chloride,  whereas  the  pseudo-globulin  remains 
insoluble.  The  pseudo-globulin  fraction  of  the  senmi  thus  behaves  in  every  way 
like  the  lecithin-globulin  compound.  The  solubility  of  the  globulin  present,  in 
serum  or  in  the  body  cells,  will  therefore  depend  upon  the  amount  of  lipoid  in 
association  with  the  globulin,  and  the  former  will  influence  the  optical  properties, 
the  electrical  charge  on  the  colloidal  particles  in  .suspension,  and  also  the  relation- 
ship of  globulin  to  electrolytes.  In  connection  with  these  observations,  it  may  be 
noted  how  important  both  constituents  of  the  complex  are  to  the  maintenance  of 
life.  During  starvation,  for  example,  the  blood  contains  a  larger  amount  of 
globuUn,  and,  after  excessive  bleeding,  the  first  constituent  of  the  blood  to  return 
to  its  normal  amount  is  the  globulin  fraction. 


CHEMISTRY   OF   THE    LEUCOCYTOZOON   SYPHILIDIS.  53 

With  regard  to  the  nature  of  the  lipoid  present  in  association  with  the  globulin, 
it  is  usually  found  to  be  lecithin.  This  lecithin  is  generally  of  the  t3^pe  described 
as  a  monoaminophosphatide,  yielding  choline  and  fatty  acids  of  the  stearyl  group, 
on  hydrolysis.  The  lecithin  is  insoluble  in  water,  and  is  so  firmly  united  to  the 
globulin  as  to  remain  undissolved  when  treated  with  ether.  The  production  of 
lecithin  is  probably  determined  by  the  processes  of  degeneration  of  cellular  material, 
which  take  place  in  diseases  in  which  effusions  may  result,  viz.,  tuberculous  infec- 
tions, malignant  disease,  and  syphilis.  In  the  production  of  milky  effusions,  it 
seems  highly  probable  that  the  destruction  of  lecithin-containing  cell  elements 
takes  place  in  the  blood  itself,  and  that  the  lecithin,  .so  formed,  diffuses  through 
the  peritoneal  membrane  into  the  serous  cavities.  This  would  explain  the  sudden 
changes  from  a  clear  efiusion  to  a  milky  one,  noted  by  some  observers,  or  the  reverse 
condition,  where  a  milky  is  later  replaced  by  a  clear  transparent  fluid 

The  resistance  to  putrefaction,  exhibited  by  all  fluids  containing  this  complex, 
is  very  striking,  in  view  of  the  fact  that  lecithin  readily  undergoes  auto-oxidation 
when  free.  The  complex  seems  to  confer  increased  stability  upon  both  constituents, 
but  at  the  .same  time  the  lecithin  is  capable  of  fully  exerting  all  its  .special  functions, 
particularly  its  influence  on  the  neutraU.sation  of  toxines  and  bacterial  growth. 
The  chemical  configuration  of  the  lecithin  molecule  possibly  accounts  for  this 
property,  since  it  contains  a  large  number  of  hydroxyl  groups  capable  of  uniting 
with  such  bodies  as  ferments,  proteins,  sugar,  and  other  lipoids.  The  power 
possessed  by  lecithin  of  rcsi.sting  putrefaction,  suggests  a  possible  function  of  this 
body  in  the  production  of  immunity. 

From  what  has  been  .stated,  it  will  be  noticed  how  close  is  the  resemblance 
between  the  pyroninophile  substance  of  the  syphilitic  parasite  and  the  colloidal 
particles  of  the  pseudo-chylous  fluid,  both  substances  being  no  doubt  identical,  and 
the  relationship  becomes  the  closer  when  the  staining  properties  of  both  are  con- 
sidered, and  for  brevity's  sake  it  need  only  be  stated  that  both  the  colloidal 
particles  and  the  .syphilitic  parasites  are  Gram  negative. 

1  Unna  u.  Golodetz  (1912),  "  Die  Bedeutung  des  Sauerstoffs  in  der  Farberei.'"    L.  Voss. 

Leipzig. 
=  Unna  (1913),  "  Biochemie  der  Haut."     G.  Fischer.     Jena. 
3  Unna  (1905),  "  Zeits.  fur  Krebsforsch."     iii,  218. 
'  Macallum  (1897),  "  Joum.  of  Physiol."  (iron),     xxii,  92. 
*  Unna  (1910),  "  Histologisoher  Atlas.''     L.  Voss.     Leipzig. 
°  Bayliss  (1906),  "  Biochemical  Journal."     i,  173. 

'  Mackenzie  Wallis  and  Scholberg  (1910),  "  Quarterly  Journ.  of  Med."     iii,  301. 
'  Mackenzie  Wallis  and  Scholberg  (1911),  "  Quarterly  Journ.  of  Med."     iv,  153. 


54 


THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 


WORKS  CONSULTED. 

Mann  (1902),  "Physiological  Histology."     Clarendon  Press.     Oxford. 

Walker  Hall  and  Herxheimer  (1905),  "  Methods  of  Morhid  Histology  and  Clin.  Pathology." 

W.  Green  &  Sons.     Edinburgh. 
Schmorl  (1909).  "  Untersuchungsmethoden."     Vogel.     Leipzig. 
Schultz    (1901),    "Die    Chemie    des    Steinkohlentheers."      Bd    2.      F.    Vieweg   u.  Sohn. 

Braunschweig. 
Abderhalden    (1910-1913),    "  Handbuch    der    Biocheui.     Arbeitsmethoden."      Urban    u. 

Schwarzenberg.     Berlin. 
Abderhalden  (1911-1914).  "  Biochemisches  Handlexikon."     J.  Springer.    Berlin. 
Oppenheimer  (1909-1913),  "  Handbuch  der  Biochemie."     G.  Fischer.     Jena. 
Hober  (1911),  "  Physikalischechemie  der  Zelle."     W.  Engelmann.     Leipzig. 
Leathes  (1910),  "  The  Fats."     Longmans,  Green  &  Co.     London. 
Dakin  (1912),  "  Oxidations  and  Reductions  in  the  Animal  Body."     Longmans,  Green  & 

Co.     London. 
Zacharias   (1909),   "  Progressus  Rei   Botanicae."     iii,  67.     G    Fischer.     Jena. 


CHAPTER   VII. 

THE  LIGHT  WHICH  THE  CHEMISTRY  OF  THE  LEUCOCYTOZOON 
SYPHILIDIS  THROWS  UPON  PREVIOUSLY  UNEXPLAINED  PHE- 
NOMENA. 

I  have  given  a  detailed  account  of  the  chemistry  of  the  Leucocytozoon 
syphilidis,  so  far  as  I  have  discovered  it,  up  to  the  present.  I  now  propose  to  apply 
this  knowledge  to  a  discussion  of  the  various  phases  of  the  organism. 

The  more  developed  the  sporozoite,  the  less  lipoid-globulin  it  has,  and  the 
more  readily  it  will  stain  with  methyl  green,  borax  methylene  blue,  etc.  The  fact 
that  it  stains  with  methyl  green  suggests  that  it  consists  of  nuclein. 

The  less  lecithin-globulin  the  sporozoite  contains,  the  less  readily  will  it  be  able 
to  give  rise  to  bodies  several  times  its  own  size.  This  appears  to  be  a  good  reason 
for  its  entering  a  cell.  In  the  case  of  syphilis,  this  happens  to  be  a  connective- 
tissue  cell,  or  an  endothelial  cell. 

From  the  protoplasm  of  the  connective-tissue  cell,  or  of  the  endothelial  cell, 
the  spore  builds  up  an  elaborate  lipoid-protein  complex.  This  complex  forms 
a  colloidal  membrane,  analogous  to  the  luicleolus  of  a  cell.  In  this  membrane, 
the  body,  or,  as  it  is  now  called,  the  trophozoite,  develops. 

In  order  to  build  up  an  elaborate  lipoid-protein  complex,  two  steps  are 
necessary.  First,  the  spore  must  break  down  the  protoplasm  of  the  cell  upon  which 
it  is  parasitic.  Secondly,  it  must  build  up  the  products  of  this  breaking  down. 
It  would  appear  that  the  process  of  lysis  was  carried  down  to  that  stage  in  which 
the  substances  formed  are  in  a  liquid  or  semi-liquid  state.  Otherwise  it  would  be 
difficult  to  explain  why  the  fully  developed  trophozoite  appears  to  lie  in  an  empty  sack. 

Finally,  all  the  protoplasm  of  the  host's  cell  is  collected  around  the  nuclear 
portion  of  the  parasite,  in  the  form  of  a  lipoid-globulin  colloidal  membrane.  The 
cell  then  begins  to  develop  into  sexual  bodies,  or  into  an  asexual  spore  cyst.  As 
might  be  expected,  in  the  case  of  a  fully  developed  trophozoite,  since  no  call  has  yet 
been  made  upon  it,  its  colloidal  membrane  possesses  strong  reducing  properties, 
and  is  highly  optically  active. 


56  THE    BIOLOGY,    CLIXICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

I  have  noticed  that  those  trophozoites  which  develop  into  asexual  spore  cysts, 
are  not  so  rich  in  lecithin-globuhn  as  those  which  develop  into  sexual  merozoites, 
that  is  to  say,  when  both  develop  in  the  same  specimen.  Therefore,  the  mode 
of  development  is  probably  somewhat  dependent  upon  the  potential  energy  a 
developing  cell  possesses,  in  the  form  of  lijjoid-proteins.  So  far,  I  have  encountered 
asexual  spore  cysts,  when  the  other  phases  are  present,  only  in  lesions  removed 
during  the  period  of  the  generalisation  of  the  virus,  and  from  what  might  be  called 
the  severest  cases,  i.e.,  if  a  ratio  exists  between  the  number  of  parasites  present 
and  the  severity  of  the  attack. 

In  such  cases,  the  greatest  number  of  connective-tissue  cells  and  endothelial 
cells  are  used  ;  and  many  more  would  be  required,  if  the  condition  of  the  host  were 
bad.  Therefore,  the  nutritive  value  of  his  cells  would  be  diminished,  with  the 
result  that  there  would  be  less  opportunity  for  the  parasites  to  form  lecithin-globulin. 
The  final  result,  if  my  original  observation  be  correct,  would  be  that  only  those 
trophozoites  which  had  found  their  way  into  the  best  connective-tissue  cells  and 
endothelial  cells  would  be  able  to  develop  into  male  and  female  bodies,  and  vice 
versa. 

Another  point  in  favour  of  the  above  statement,  is  the  fact  that  those  connective- 
tissue  cells,  and  endothelial  cells,  in  which  asexual  spore  cysts  are  developing,  appear 
more  degenerate  than  those  in  which  sexual  bodies  are  developing.  So  a  common 
stage  in  the  development  of  both  is  reached,  when  the  asexual  spore  cyst  looks  as  if 
it  was  extracellularly  situated,  while  the  sexual  bodies  are  still  obviously  intra- 
cellular. When  the  asexual  stage  is  the  only  stage  which  develops,  the  parasitic 
bodies  are  much  bigger,  they  are  much  richer  in  lipoid-globulin,  not  so  many 
sporozoites  are  formed,  but  the  cells  in  which  the  initial  stages  develop  degenerate 
very  quickly,  with  the  result  that  the  asexual  spore  C3^sts  generally  appear  to  be 
extracellularly  situated.  It  is  not  yet  absolutely  clear,  whether  in  those  cases  in 
which  the  asexual  phases  only  are  found,  the  asexual  phases  are  those'*  of  the 
Leucocyiozoon  si/pJiilidis  or  of  another  coccidial  protozoon  ;  nor  why  only  the 
asexual  stage  should  be  perpetuated. 

As  the  trophozoite  buds  into  the  sexual  merozoites,  the  reducing  action  and 
optical  activity  diminish,  owing  to  the  energy  which  has  been  expended  in  their 
development.     When  the  sexual  bodies  are  ripe,  the  cell  sets  them  free. 

These  freed  bodies  are  now  male  and  female  gametocytes.  It  will  be  found 
that  the  reducing  action  and  optical  activity  are  much  more  pronounced  in  the 
male  cells  than  in  the  female  cells. 

The  number  of  merozoites  formed  by  a  trophozoite  varies,  and  no  definite 
ratio  exists  between  the  number  of  the  male  and  female  bodies  which  are  developed. 


PROBLEMS   CLEARED   UP   BY   CHEMISTRY   OF   LEUCOCYTOZOON   SYPHILIDIS.  57 

By  analogy,  it  iiiight  be  suggested  that  the  same  factors  which  are  responsible 
for  the  development  of  a  trophozoite  into  sexual  bodies  on  the  one  hand,  and  into 
asexual  spore  cysts  on  the  other,  also  influence  the  development  of  one  sexual 
merozoite  in  preference  to  the  other. 

It  now  appears  possible  to  explain  not  only  why  the  male  cell  is  richer  in 
lecithin-globulin  than  the  female  cell,  but  also  why  it  develops  at  the  expense  of 
the  host's  cells.  The  possibility  is  suggested  at  once  by  the  fact  that  the  male 
cell  gives  rise  to  cells  which  are  actively  motile,  and  which  have  an  important 
function  to  perform,  while  the  female  cell  is  passive  throughout.  Probably  the  male 
gametocytes  which  develop  extracellularly  are  those  which  are  richest  in  lipoid- 
globulin,  or  which  are  in  the  best  way  of  living  on  the  material  in  which  they  are 
circulating. 

I  have  noticed  extracellular  development  in  a  brain  from  a  case  of  degenerative 
encephalitis,  a  most  likely  place,  when  one  realises  how  rich  the  nerve  cells  are  in 
lipoid-proteins.  A  very  interesting  point  which  I  have  been  able  to  bring  out  from 
the  study  of  the  chemistry  of  the  Spirochaeta  pallida,  is  that  the  spirochaetae 
which  have  developed  extracellularly  differ  from  those  which  have  developed  intra- 
cellularly.  The  characteristics  common  to  both  are  less  pronounced  in  the  former, 
than  in  the  latter. 

Spirochaetae  which  have  developed  intracellularly  stain  pink  with  Giemsa, 
while  the  others  stain  more  blue.  The  former  stain  pink-red  with  borax  methylene 
blue,  and  brilhant  crystal  blue,  etc.,  while  the  latter  show  less  affinity  for  the  methy- 
lene red  portion  of  the  dyes  mentioned.  This  means  that  their  reducing  action  is 
less.  The  intracellularly-developed  spirochaetae  take  up  more  dextrose  than  the 
others.  They  stain  more  deeply  with  basic  dyes,  which  suggests  that  they  are 
more  acidic.  Therefore,  those  spirochaetae  which  have  developed  in  large  mono- 
nuclear leucocytes  are  richer  in  lipoid-proteins  than  those  which  have  not  so 
developed.  From  the  fact  that  the  former  will  take  up  more  dextrose  than  the 
latter,  it  may  be  assumed  that  their  adsorptive  powers  are  greater. 

Since  the  reducing  action  is  most  marked  in  the  spirochaetal  phase  of  the 
leucocytozoon,  and  the  same  applies  to  the  basophilic  action,  there  can  be  no 
doubt  that  the  fatty  acid  tends  to  be  more  unsaturated  than  that  which  is  met 
with  in  the  lipoid  part  of  the  other  phases. 

Considering  the  adsorptive  capacity  of  the  Spirochaeta  pallida,  with  the  other 
points  just  mentioned,  the  suggestion  offers  itself  that  the  Spirochaeta  pallida 
contains  a  lipoid-protein  with  oleic  acid,  or  some  other  allied  unsaturated  fatty 
acid,  in  its  molecule. 

As  stated  on  p.  17,  an  acid  is  necessary  for  fertilisation,  as  I  have  already 


58  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   SYPHILIS. 

pointed  out  that,  when  the  spirochaeta  has  entered  the  female  cell,  a  mantle 
develops  over  the  whole  cell  and  it  takes  the  methylene  red  part  of  the  dye.  In 
fixed  specimens,  impregnated  females  are  much  more  markedly  pyroninophile  and 
stain  much  more  deeply  with  basic  dyes  than  the  female  ganietocytes  do. 

Therefore,  during  impregnation,  the  female  cell  obtains  from  the  male  an  acid 
and  strongly  reducing  substance — a  lipoid-protein,  the  lipoid  portion  of  which 
contains,  besides  a  saturated  fatty  acid,  a  trace  of  an  unsaturated  fatty  acid. 

The  mantle  becomes  part  and  parcel  of  the  protoplasm  of  the  cell,  which  in 
toto  forms  a  colloidal  membrane  analogous  to  a  nucleolus,  and  in  which  the  nuclear 
part  divides  and  subdivides  into  spores. 

The  nearer  one  gets  to  the  spore  stage,  the  less  marked  is  the  lipoid-jDroteiu 
envelope. 

Before  closing  this  chapter,  I  should  hke  to  refer  to  those  spirochaetae  which 
are  sometimes  to  be  seen,  containing  30  or  more  coils.  These  very  long  spirochaetae 
are  often  bent  at  right  angles  ;  each  leg  of  the  angle  may  move  independently  of  the 
other.  At  the  junction  of  the  legs  the  coils  may  be  less  marked,  for  it  is  almost 
straight,  and  thinner  than  elsewhere.  Some  specimens  are  seen,  in  which  the  two 
sides  of  the  angle  bend  over,  approximate,  and  lie  parallel  to  each  other. 

Many  observers  state  that  these  are  spirochaetae  dividing,  and  I  should 
think  this  is  very  possibly  the  case,  although  I  have  never  been  successful  in  seeing 
the  actual  occurrence  of  division.  The  point  to  which  I  wish  to  draw  attention 
is,  that  these  spirochaetae  have  developed  extracellulaiiy.  The  extraceUularly- 
developed  spirochaetae  are  probably  not  rich  enough  in  basophihc  hpoid-proteins 
for  impregnation,  therefore  it  is  reasonable  to  suggest  that  they  expend  their 
energy  in  dividing,  just  as  female  cells  may  divide. 

A  phenomenon  which  I  am  at  present  entirely  luiable  to  explain  is,  the  extrusion 
of  the  polar  bodies.  In  the  Leucocytozoon  syphilidis  they  are  extruded  after 
impregnation,  and  they  consist  chemically  of  a  lipoid-protein  protoplasm  with  a 
small  mass  of  nuclein  in  the  centre  (Plate  13  (1 ) ).  An  observation  which  adds  to  the 
difficulty  of  an  explanation,  is  that  of  Loeb,  namely,  that  cells  which  he  caused 
to  develop  by  parthenogenesis  also  extruded  polar  bodies. 


CHAPTER   VIII. 

THE   CULTIVATION   OF   THE    SPIROCHAETA    PALLIDA,   AND   THE 
METHODS  OF  DEMONSTRATING  THIS  ORGANISM. 

Since  Schereschewskv,i  -  in  the  j'ear  1909,  published  a  paper  in  which  he  stated 
that  he  was  able  from  human  syphilitic  material  to  grow  a  mixed  culture  of  spiro- 
chaetae,  the  number  of  observers  who  have  come  into  the  field  is  alread}'  legion. 
It  is  impossible  to  mention  everybody,  or  even  to  give  a  full  bibliography  of  the 
subject,  so  in  this  chapter  onl}'  the  most  important  names  and  references  will  be 
given.  The  men  who  have  done  most  work  in  this  direction  are  Noguchi,^  4  5  g  7  8  9 
Schereschewsky,^  -  Miihlens.i"  W.  H.  Hoffmann,"  ^-  Tomasczewski,!-''  Sowade,^* 
Nakano,^^  Shamine,^^  Bruckner  and  Galasesco,^^  Boas,^^  and  Proca,  Danila  and 
Stroc.^'  The  media  which  these  observers  used  can  be  divided  into  three  groups  : 
(a)  coagulated  horse  serum ;  (b)  serum  water  with  fresh  sterile  animal  material ; 
(c)  ascites  agar,  with  fresh  sterile  animal  material. 

Most  of  the  early  work  was  done  with  the  coagulated  horse  serum — in  fact, 
this  was  the  medium  used,  with  certain  modifications,  by  all  the  observers,  with  the 
single  exception  of  Noguchi,  who  not  only  used  media  (6)  and  (c),  but  also  invented 
them.  The  modifications  made  with  the  coagulated  horse  serum  were  of  not  much 
importance.  Shamine^®  added  a  small  quantity  of  nucleinate  of  soda,  and  Nakano^^ 
added  peptone  agar. 

The  observers  already  mentioned  succeeded  in  growing  spirochaetae,  not  only 
from  human  syphilitic  material,  but  also  from  inoculated  animal  material  as  well.  As 
Noguchi's  work  difiers  so  much  from  the  work  of  the  other  observers,  who  more 
or  less  copied  one  another,  the  whole  history  of  the  cultivation  of  the  Sjnrochaeta 
pallida  can  be  described  under  the  names  of  Noguchi  and  the  rest,  or  American 
and  Continental. 

The  Continental  observers  did  not  employ  those  strict  anaerobic  conditions,  which 
Noguchi  found  to  be  so  essential,  and,  from  the  most  recent  work,  it  woidd  appear 
that  Noguchi  was  the  only  one  who  was  able  to  grow  pure  cultures  of  the  organism. 
Noguchi  found,  that  for  getting  a  pure  culture  of  the  Sjnrochaeta  jjallida  from 


60  THE    BIOLOGY,    CLINICAL   ASPECT   A\D    TREATMENT   OF   SYPHILIS. 

inoculated  animal  material,  the  tissue  serum  water  medium  was  tlie  best,  but  in  order 
to  obtain  a  pure  culture  from  human  material,  owing  to  the  almost  certain  presence 
of  a  secondary  infection,  that  the  tissue  ascites  agar  was  the  better  of  the  two. 
Noguchi  was  also  the  first  observer  to  produce  syphilitic  lesions  in  animals  by 
means  of  inocidations  from  his  spirochaetal  cvdtures. 

In  comparing  the  spirochaetae  grown  by  the  various  observers,  great  differences 
appear  to  exist.  The  spirochaetae  cultured  by  Miihlens  and  Hoffmann  had  a  foul 
odour,  and  only  flourished  near  the  surface  of  the  cultm'e  medium,  i.e.,  they 
preferred  aerobic  to  anaerobic  conditions.  Noguchi's  spirochaetae,  on  the  other 
hand,  had  no  odour,  and  would  only  develop  under  the  strictest  anaerobic  conditions. 
In  spite  of  these  fundamental  differences  Miihlens  and  Hoffmann  were  as  successful 
in  producing  syphilitic  lesions  in  animals,  by  inoculating  their  cultured  material,  as 
Noguchi  was  with  his.  There  can  be  only  two  explanations  of  this  discrepancy, 
and  the  two  I  am  about  to  mention  are  both  probably  correct.  One  is  that, 
because  the  animal  develops  a  lesion  in  which  spirochaetae  can  be  found,  this  fact 
is  no  criterion  that  that  animal  is  suSering  from  syphilis.  The  other  is,  that  both 
cultures  probably  contained  the  spores  of  the  Leucocytozoon  syphilidis,  and  that 
these,  when  inoculated  into  a  suitable  medium,  developed  into  spirochaetae. 
Because  spirochaetae  were  present  in  all  the  cultures  does  not  exclude  the  presence 
of  smaller  insignificant  bodies,  which  could  be  easily  overlooked,  and  it  does  not 
prove  that  the  animal  infection  was  directly  due  to  the  spirochaetae  themselves. 
It  is  quite  conceivable  that  a  patient  could  develop  diphtheria,  if  a  colon}'  or  two 
contaminated  a  culture  of  staphylococci  for  instance,  which  had  been  used  for 
inoculation  purposes,  but  it  would  not  follow  that  the  diphtheria  was  due  to  the 
staphylococci  just  because  the  diphtheria  bacillus  had  been  overlooked.  In  this 
case,  we  are  familiar  enough  with  the  conditions  not  to  be  misled.  "\Miile  in  the 
former  case,  we  do  not  know  enough  about  the  cause  of  syphilis  to  suspect  that  there 
is  another  factor  existing,  which  requires  to  be  taken  into  consideration. 

All  observers  appear  to  have  attached  tremendous  importance  to  the 
morphology,  as  serving  to  distinguish  the  various  spirochaetae,  and  they  do  not 
seem  to  have  paid  any  attention  to  the  variations  which  might  have  been  produced 
by  the  conditions  under  which  they  were  growing.  Morphology  helps  us  little  in 
differentiating  the  various  bacilli,  and,  moreover,  we  all  know  how  a  bacillus  may 
alter  its  form,  according  to  the  conditions  under  which  it  is  growing. 

Since  success  has  crowned  the  efEorts  to  cidture  spirochaetae,  their  number 
has  certainly  increased,  as  a  perusal  of  Noguchi's  papers  will  prove.  In  a  recent 
article,  Noguchi  mentions  the  Spirochaeta  calligymm,  which  appears  to  have  some 
importance,    as   Noguchi    says    it   stands    midway   between   the   pallida    and   the 


CULTIVATION   AND    DEMONSTRATION    OF    SPIROCHAETA   PALLIDA.  61 

refringens.  The  other  points  brought  forward  about  this  species  are  that  it  resembles 
the  Spirochaeta  pallida  not  only  morphologically,  but  also  that  its  growth  in  culture 
emits  no  odour.  It  is  said  to  be  non-pathogenic,  but  it  frequently  exists  in  a  state  of 
symbiosis  with  the  Spirochaeta  pallida.  According  to  Noguchi,  if  one  wishes  to 
know  whether  the  Spirochaeta  pallida  is  present  in  a  culture  in  which  other  spiro- 
chaetae  already  exist,  such  as  the  calligyrum,  refringens,  microdentium,  and 
mucosum,  all  that  is  necessary  is  to  remove  the  piece  of  animal  tissue  and  to 
supplant  the  anaerobic  by  aerobic  conditions,  when  the  other  spirochaetae  will 
flourish,  while  the  Spirochaeta  pallida  vanishes.  Reversing  the  position  will  not 
result  in  the  opposite  being  maintained.  Such  a  procedure  does  not  seem  to  me 
to  be  very  conclusive,  and,  from  the  experiments  I  have  undertaken  myself,  I  am 
rather  inclined  to  the  view  that  many  of  the  spirochaetae  obtained  in  culture  are 
not  distinct  species,  but  various  phases  in  the  development  of  the  Spirochaeta 
jyallida.  I  removed  some  young  chancres,  after  thoroughly  sterilising  the  surface, 
and  put  some  into  ascites  broth  with  animal  tissue,  and  some  into  ascites  broth 
without  animal  tissue.  In  both  cases  the  tubes  were  incubated  at  37°  C,  mider 
strict  anaerobic  conditions.  The  difference  was  very  noticeable.  In  the  tubes 
which  contained  animal  tissue,  typical  Spirochaetae  pallidae  were  obtained  in  large 
quantities  ;  but,  in  the  tubes  without  animal  tissue,  the  spirochaetae  were  morpho- 
logically of  the  refringens  type,  and  the  development  of  these  from  the  coccal  bodies 
which  I  have  already  described  was  quite  evident  {vide  Page  9  and  Plate  2). 
None  of  the  tubes  emitted  any  odour,  which  strongly  favoured  the  view  that  in 
both  instances  one  was  dealing  with  the  syphilitic  spirochaeta. 

Noguchi's  point,  that  an  extract  of  Spirochaetae  pallidae  will  only  fix  com- 
plement in  the  presence  of  antibody,  provided  that  that  antibody  comes  from  late 
cases  of  syphilis,  fits  in  well  with  some  of  the  factors  which  I  have  brought  forward 
(vide  Chapter  X.)  as  influencing  the  Wassermann  reaction,  and  as  explaining 
its  modus  operandi.  In  my  chemical  work  on  the  Leucocytozoon  syphilidis,  I 
showed  that  the  envelope  of  the  Spirochaeta  pallida  contained  an  unsaturated  fatty 
acid,  and,  in  my  work  on  the  rationale  of  the  Wassermann  reaction,  that  a  trace  of 
a  free  fatty  acid,  especially  if  it  were  an  unsaturated  one,  prevented  the  adsorption 
of  complement,  and  that  an  excess  had  an  anti-complementary  action. 

In  all  cases  of  syphilis,  the  reagin  is  a  lipoid-globulin,  but  the  ratio  between 
the  lipoid  and  globulin  particles  varies  in  the  different  stages.  In  the  early  stages, 
the  globulin  particles  are  in  excess  of  the  lipoid,  while  in  the  late  stages  the  lipoid 
particles  are  markedly  increased — whether  in  excess  of  the  globulin  particles  or  not, 
cannot  be  accurately  determined  ;  but  the  point  is,  that  the  lipoid  particles  are  more 
numerous  in  the  late  stages  of  syphilis.     The  richer  a  molecule  is  ia  Hpoids,  the 


62  THE    BIOLOGY,    CLINICAL    ASPECT   AND    TREATMENT    OF    SYPHILIS. 

more  fatty  acid  particles  it  contains,  and,  when  there  are  several  fatty  acid  particles, 
it  is  very  easy  for  one  or  more  to  be  broken  off  from  the  molecule.  The  broken 
off  fatty  acid  particles  from  the  reagin  molecule,  plus  those  contained  in  pure 
spirochaetal  antigen,  might  easily  suffice  to  constitute  an  excess  of  fatty  acid  in  the 
serum,  and  this  would  have  a  marked  anti-complementary  action — hence  positive 
reaction  in  late  cases,  negative  in  early. 

For  full  details  as  to  the  preparation  of  the  media,  the  reader  should  consult 
Noguchi's  articles,  which  are  given  in  the  bibliography  at  the  end  of  this  chapter ; 
but,  before  closing  this  subject,  I  should  like  to  draw  attention  to  an  ingenious 
method  for  cultivating  the  spirochaetae  under  anaerobic  conditions,  which  has 
been  devised  by  McLeod  and  Soga.-° 

A  tube,  which  may  be  chosen  of  any  size  that  is  required,  is  fitted  with  a 
perforated  rubber  cork.  A  piece  of  glass  tubing  is  introduced  to  within  a  short 
distance  of  the  lower  end  of  the  cork.  Immediately  above  the  cork,  the  tubing 
is  drawn  out  into  a  capillary,  which  is  bent  over  at  an  acute  angle.  This  tube  is 
now  filled  to  half  or  two-thirds  of  its  depth  with  peptone  bouillon.  After  the  tube 
has  been  sterilised,  a  portion  of  sterile  rabbit's  kidney  is  introduced.  Then  a  piece 
of  cotton  wool,  which  has  been  threaded  through  a  glass  bead,  is  soaked  with  the 
material  which  it  is  desired  to  inoculate,  and  this  is  then  dropped  into  the  tube. 
Then  ascites  fluid  is  run  in  with  a  pipette,  till  the  level  of  the  liquid  in  the  tube  is 
within  a  distance  of  its  mouth,  which  corresponds  to  half  of  the  depth  of  the  cork. 
The  tube  is  now  corked  tightly,  and  this  causes  the  fluid  to  rise  into  the  glass 
tubing,  and  when  it  has  reached  the  curve,  the  free  end  is  sealed  in  a  flame. 

The  great  advantages  of  this  method  are,  that  fluid  can  be  withdrawn  for 
examination  at  any  stage,  with  no  risk  of  contamination,  and  that  subcultures  can 
be  easily  made.  All  that  is  necessary  is  to  break  off  the  tip  of  the  glass  tubing, 
draw  off  some  fluid  with  a  pipette,  and  seal  up  the  tube  again. 

Methods  of  Demonstrating  the  Spirochabta  Pallida. 

The  Spirochaeta  pallida  can  be  demonstrated  alive,  unstained,  by  the  dark- 
ground  illumination  method,  or  stained  with  borax  methylene  blue,  for  the 
methylene  red  part  of  which  the  organism  shows  an  affinity. 

For  the  former  method,  a  paraboloid  condenser  is  required  and  a  powerful 
illumination,  for  preference  a  small  arc  lamp.  A  drop  of  the  secretion  from  the 
sore  is  placed  upon  a  cover  slip  and  this  is  pressed  on  to  the  slide  as  firmly  as  possible. 
The  slide  is  then  placed  on  the  paraboloid  condenser  upon  which  a  drop  of  cedar 
wood  oil  has  been  put.     Another  drop  of  cedar  wood  oil  is  placed  on  the  upper 


CULTIVATION   AND    DEMONSTRATION    OF   SPIROCHAETA    PALLIDA.  65 

surface  of  the  cover-slip  and  the  specimen  is  examined  with  a  l/12th  or  a  l/16th 
oil  immersion  lens.  The  spirochaetae  appear  white  against  a  black  background. 
For  the  latter  method  no  special  apparatus  is  required.  A  film  of  borax  methylene 
blue  is  made  upon  a  fat  free  slide  and  is  allowed  to  dry  in  the  air,  then  a  drop  of  the 
secretion  to  be  examined  is  placed  upon  a  cover-slip  which  is  inverted  upon  the 
dye  containing  surface  of  the  slide. 

This  method  has  enormous  advantages  over  the  former  since  the  other  phases 
of  the  Leucocytozoon  sypMUdis  can  be  demonstrated  as  well,  and  the  observer  may 
be  fortunate  enough  to  witness  the  act  of  impregnation. 

The  spirochaeta  pallida  can  be  demonstrated  dead,  unstained  by  the  Indian 
ink  method,  or  stained  with  a  silver  preparation,  Giemsa's  stain,  gentian  violet,  &c. 

For  the  Indian  ink  method  a  droj")  of  the  secretion  is  mixed  with  a  drop  of 
water,  and  a  drop  of  Indian  ink  on  a  slide.  A  film  is  then  made,  allowed  to  dry 
and  on  examination  the  spirochaetae  stand  out  white  against  a  dark  background. 

When  a  film  cannot  be  examined  at  once,  or  when  it  is  necessary  to  send  it 
somewhere  else  to  be  examined,  the  best  method  to  use  is  Fontana's.^^  The  films 
are  dried  in  the  air  and  then  bathed  several  times  with  what  is  known  as  Huge's 
fluid  for  about  a  minute. 

Huse's  fluid  consists  of : — 


•'b^ 


Acetic  acid  ...         ...         ...         ...         ...         1  part. 

Formalin     ...         ...         ...         ...         ...         ...         2     ,, 

Distilled  water       100     „ 

The  films  are  washed  with  water,  and  then  treated  with  a  5  per  cent,  solution 
of  tannic  acid  in  a  1  per  cent,  aqueous  solution  of  carbolic  acid.  'WTiile  this 
mordant  is  on  the  slide,  the  slide  is  heated,  left  for  30  seconds  and  then  washed 
again  with  water.     Without  drying  the  silver  preparation  is  next  applied. 

The  silver  preparation  consists  of  a  0"2.5  per  cent,  aqueous  solution  of  silver 
nitrate,  to  which  just  sufficient  ammonia  has  been  added  to  produce  a  slight 
turbidity. 

When  the  silver  preparation  has  been  applied  the  slide  is  once  more  heated 
and  then  left  for  about  a  minute.  The  slide  is  then  washed,  dried  and  mounted 
in  Canada  balsam.     The  spirochaetae  appear  black  against  an  unstained  background. 

This  method  is  distinctly  to  be  preferred  to  any  method  of  staining  with  dyes, 
such  as  eosine  methylene  blue,  gentian  violet,  &c.,  which  give  very  uncertain 
results. 

In  section,  the  Spirochaeta  pallida  can  be  best  demonstrated  by  Noguchi's^^ 
modification  of  Levaditi's  silver  nitrate  method.     The  tissue  must  be  small  and 


64  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

not  thicker  than  7  mm.     The  tissue  is  first  placed  for  five  days  at  room  temperature 

in  the  following  mixture  : — 

Formalin 10  parts. 

Pyridine      10      ,, 

Acetone       ...         ...         ...         ...         ...         ...  25      ., 

Alcohol        25      ., 

Distilled  water       30       „ 

The  tissue  is  then  washed  in  distilled  water  for  24  hours,  and  again  for  24  hours, 
after  it  has  been  for  three  days  in  96  per  cent,  alcohol. 

The  following  stages  are  performed  in  dark  vessels  : — 

1.  Three  days  at  37°  C,  or  five  days  at  room  temperature,  in  a  1'5  per  cent. 

solution  of  silver  nitrate. 

2.  Wash  in  distilled  water  for  2  hours. 

3.  Reduce  for  24-48  hours  at  room  temperature  in  a  4  j)er  cent,  solution  of 

pjTogallic   acid   to  which  has  been  added  -gVth  of  its  volume  of  formalin 
(5  per  cent.). 

4.  Wash  w-ell  in  distilled  water. 

5.  80  per  cent,  alcohol,  24  hours. 

6.  95  per  cent,  alcohol,  3  days  ;    alcohol  must  be  renewed  daily. 

7.  Absolute  alcohol,  2  days. 

8.  Xylene,  paraffin,  &c. 

The  spirochaetae  stain  black,  and  the  tissue  cells  yellow. 

I  Schereschewsky  (1909),  "  Dent.  med.  "Woch."     xxxv,  835. 
-  Sebereschewsky  (1913),  "  Compt.  rend.  Soc.  Biol."     Ixxv,  22-2 
3  Noguchi  (1911),  .Touru.  "  Amer.  Med.  Assoc."     Ivii,  102. 
*  Nog\iclii  (1911),  "  MiincU.  med.  "Woch."     Iviii,  1550. 
=  Noguchi  (1912),  "  Jouru.  Exper.  Med."     xv,  90. 
0  Noguchi  (1912),  "  Jonrn.  Exper.  Med."     xv,  201. 
^  Noguchi  (1913),  "  Journ.  Exper.  Med."     xvii,  89. 

8  Noguchi  (1912),  "Journ.  Exper.  Med."     xv,  211.  ■* 

a  Noguchi  (1914),  "  Archiv.  f.  Derm.  u.  Syph."     cxix,  181. 
>"  Muhleus  (1910),  "  Klin.  Jahrb. '     xxiii,  339. 
"  Hoffmann  (1911),  "  Deut.  med.  Woch."     xxxvii,  1546. 

12  Hoffmann  (1911),  "  Zeitschr.  f.  Hyg."     Iviii,  27. 

'3  Tomasczewski  (1912),  "  Berl.  klin.  Woch."     xlix,  1556. 

"  Sowade  (1914),  "Arch.  f.  Derm.  u.  Syph."     cxix,  189. 

1"  Nakano  (1912),  "  Deut.  med.  Woch."     xxxix,  13.33. 

"■■  Shamine  (1912),  "  Zentralbl.  f.  Bakt."     Ixv,  311. 

"  Bruckner  et  Galasescb  (1910),  "  Compt.  reud.  Soc.  Biol."    Iviii,  684.  .   — 

15  Boas  (1911),  "  Nord.  Med  Archiv."     ii,  53. 

13  Proca,  Danila  et  Stroe  (1912),  "Compt.  rend.  Soc.  Biol."  Ixxii,  495. 
^MoLeod  and  Soga  (1914),  "Journ.  of  Path,  and  Bact.'  six.  210. 
-'I  Fontana  (1913),  "Dermatol.  Woch."     hi,  301. 

■■'S  Noguchi  (1913),  "Miuich.  med.  Woch."     Ix,  737. 


CHAPTER  IX. 
TECHNIQUE   OF  THE   WASSERMANN  REACTION. 

Patient's  Serum. 

The  blood  is  best  withdrawn  from  a  vein.  Antiseptics  used  for  cleansing  the 
skin  should  be  allowed  to  dry,  before  the  needle  is  inserted,  since  a  trace  of  alcohol 
or  ether  in  the  serum  may  alter  the  reaction.  Blood  should  not  be  withdrawn 
while  the  patient  is  under  an  anaesthetic,  as  anaesthetics  tend  to  make  negative 
sera  give  a  positive  reaction — chloroform  especially  has  this  effect. 

The  blood  should  be  allowed  to  stand  in  a  warm  place,  until  the  serum  separates 
off.  The  serum  should  then  be  taken,  and  inactivated  in  an  incubator  or  a  water 
bath  at  57°  C.  for  half  an  hour.  If  a  blood  is  to  be  sent  by  post,  only  the  serum 
should  be  sent.  When  the  test  is  to  be  carried  out,  the  serum  should  be  diluted 
1  in  10,  or  1  in  5,  with  saline  (0"9  per  cent.). 

Antigen. 

The  best  antigen  is  an  alcoholic  extract  of  a  congenital  s'y-philitic  liver.  As 
so  many  are  on  the  market,  it  is  not  worth  while  to  prepare  one's  own.  For  some 
time  past,  I  have  used  the  antigen  supplied  by  the  SachsLsches  Serumwerk,  and  it 
has  always  given  constant  results.  Before  use,  it  is  diluted  with  saline  1  in  10.  The 
saline  should  be  added  gradually,  and  the  diluted  liquid  should  be  gently  agitated 
after  each  addition. 

Complement. 

Complement  is  best  obtained  from  a  guinea  pig.  As  deep  anaesthesia  destroys 
complement,  the  best  plan  is  to  render  the  guinea  pig  unconscious  by  a  knock  on 
its  head.  An  incision  is  made  down  the  middle  line  of  neck,  the  carotids  are 
dissected  out,  cut,  and  allowed  to  bleed  into  a  tube.  This  procedure  will  bleed 
the  anhnal  to  death.  The  blood  is  put  into  an  incubator  at  37°  C,  and  allowed 
to  remain  until  the  serum  separates  off.  It  is  best  not  to  centrifuge  complement. 
Complement,  as  a  rule,  will  not  remain  fresh  longer  than  36  hours. 

E  2 


66  the  biology,  clinical  aspect  and  treatment  of  syphilis. 

Amboceptor. 

Amboceptor  is  the  serum  of  rabbits  which  have  been  immunised  against  the 
red  blood  corpuscles  of  the  sheep.  Owing  to  the  trouble  entailed  in  immunising 
rabbits,  the  best  plan  is  to  use  the  dried  amboceptor  prepared  by  the  Sachsisches 
Serumwerk.  It  is  packed  in  tubes  containing  O'l  grm.,  and  the  titer  is  constant, 
namely,  0"0003.  The  dried  serum,  before  use,  is  added  to  2  c.c.  of  distilled  water, 
and  then  made  up  to  10  c.c.  with  saline.  The  dried  senmi  dissolves  slowly,  and  it 
should  be  shaken  briskly.  Solution  will  take  place  more  rapidly,  if  some  fragments 
of  the  containing  tube  are  allowed  to  fall  into  the  test-tube  in  which  the  solution 
is  made.  These  fragments  of  glass  break  up  the  pieces  of  dried  serum,  and  so  a 
larger  surface  is  offered,  a  condition  highly  favourable  to  rapid  solution. 

Sheep's  Red  Blood  Corpuscles. 

Sheep's  blood  is  obtained  from  the  slaughter-house,  mixed  with  saline  and 
then  centrifuged.  The  fluid  is  then  pipetted  off,  and  the  deposit  is  shaken  again 
with  saline,  and  centrifuged.  This  process  is  repeated  about  half-a-dozen  times, 
until  the  supernatant  fluid  is  quite  colourless,  which  shows  that  the  red  blood 
corpuscles  in  the  deposit  are  well  washed.  Before  use,  the  red  blood  corpuscles 
are  diluted  1  in  20  with  saline,  i.e.,  a  5  per  cent,  emulsion.  It  is  well  to  add  the 
corpuscles  to  some  saline,  and  then  add  the  remainder  of  the  saline.  In  this  way, 
the  tendency  of  the  corpuscles  to  cling  to  the  tube,  is  overcome. 

Before  the  test  can  be  carried  out,  the  strength  of  the  complement  must  be 
ascertained. 

Two  tubes,  A  and  B,  are  taken.  A  contains  complement  1  in  30,  and  B  con- 
tains complement  1  in  40. 

Six  tubes  are  placed  in  a  row  and  numbered  5,  10,  15,  20,  30,  40. 

"6  c.c.  of  the  contents  of  tube  A  are  transferred  to  tube  5.  To  this  are  added 
'1  c.c.  of  the  1  in  10  dilution  of  amboceptor,  "1  c.c.  of  1  in  20  emulsion  of  sheep's 
red  blood  corpuscles,  '  1  c.c.  of  1  in  10  dilution  of  antigen.  The  contents  of  tube  5 
are  then  made  up  to  1  c.c.  by  adding  "  1  c.c.  of  saline.  Therefore,  the  1  c.c.  of  fluid 
in  tube  5  contains  "6  c.c.  of  1  in  30  complement,  that  is,  6/30  of  complement ;  there- 
fore, in  tube  5  the  dilution  of  complement  is  1  in  5. 

In  tube  10,  "3  c.c.  of  the  contents  of  tube  A  are  placed. 
1.5   "2  A. 

,,       oO,  "1  ,,  ,,  A  ,, 

„      20,  -2  „  „  B 

„      40,  -1  „  „  B 


TECHNIQUE    OF   THE    WASSERMANN  .S   REACTION. 


67 


To  each  of  these  are  added  antigen,  amboceptor  and  red  blood  corpuscles,  as 
to  tube  5  above,  and  the  total  content  in  each  is  made  up  to  1  c.c.  by  adding  saline. 
Therefore  : — 

Tube  10  contains  3/30  of  complement  =  dihition  1  in  10. 

=       „       1  „  30. 
=       ,.       1  „  20. 

=  „  1      :,     40. 

The  operation  may  be  expressed  shortly  : — 

Tube  A     "1  c.c.  complement  +  2"9  c.c.  saline. 
,,     B     '1  c.c.  „  +3*9  c.c.      ,, 


15 

>) 

2/30 

30 

j» 

1/30 

20 

yt 

2/40 

40 

n 

1/40 

Tube— 

5. 

10. 

15. 

20. 

30. 

40. 

c.c. 

c.c. 

c.c. 

c.c. 

c.c. 

c.c. 

From  tube  A 

0-6 

0-3 

0-2 

01 

From  tube  B 

... 

0-2 

01 

Amboceptor     ... 

0  1 

01 

01 

01 

01 

01 

Antigen            

01 

01 

01 

01 

01 

01 

Corpuscles        

0-1 

01 

01 

0-1     ! 

0-1 

01 

Saline 

01 

0-4 

0-5 

0-5       j 

0-6 

OG 

Total 

10 

10 

10 

10 

10 

10 

The  test  tube  rack  is  then  placed  in  an  incubator  at  37°  C,  for  from  20  minutes 
to  half-an-hour.  If  the  complement  is  good,  in  20  minutes  there  should  be  complete 
haemolysis  in  tube  30,  and  in  half-an-hour  complete,  or  nearly  complete,  haemolysis 
in  tube  40.  If  this  is  the  case,  the  strength  of  complement  to  be  used  in  the  test 
should  be  1  in  12. 

If  there  is  haemolysis  in  tube  20  in  20  minutes,  and  in  tube  30  in  half-an-hour, 
the  complement  should  be  diluted  1  in  10.  If  there  is  haemolysis  in  tube  15  in 
20  minutes  and  in  tube  20  in  half-an-hour.  the  complement  should  be  diluted 
linS. 

If  there  is  haemolysis  in  tube  10  in  20  minutes  and  in  tube  20  in  half-an-hour, 
the  complement  should  be  diluted  1  in  5.  With  complement  so  weak  as  this,  very 
unsatisfactory  results  are  obtained,  since  guinea-pig's  serum  not  infrequently  has 
a  strong  haemolytic  action  on  sheep's  red  blood  corpuscles.  Under  such 
circimistances  it  is  best  to  kill  another  guinea-pig. 


68  IHE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   SYPHILIS. 

Before  any  series  of  tests  the  complement  should  always  be  most  carefully 
titrated. 

A  rack  is  then  obtained,  marked  A,  1,  lA,  2,  2A,  etc.,  and  the  tubes  should 
always  have  a  diameter  of  not  less  than  1  centimetre,  so  that  the  contents  can  be 
easily  shaken  and  mixed.  In  A  is  placed  1/10  c.c.  of  a  1  in  10  dilution  of  antigen 
and  1/10  c.c.  of  the  titrated  complement  dilution. 

In  1  is  placed  1/10  c.c.  of  serum  No.  1,  diluted  1  in  10,  or  1  in  .5,  and 
1/10  c.c.  of  the  titrated  complement  dilution. 

In  lA  is  placed  1/10  c.c.  of  serum  No.  1  diluted  1  in  10,  or  1  in  5,  1/10  c.c. 
of  antigen  diluted  1  in  10,  and  1/10  c.c.  of  the  titrated  complement  dilution. 

To  each  tube  5/10  c.c.  of  saline  is  added.  The  tubes  are  then  shaken,  and 
the  rack  is  placed  in  an  incubator  at  37°  C.  for  f  to  IJ  hours. 

After  incubation,  to  each  tube  is  added  1/10  c.c.  of  amboceptor  diluted 
1  in  10,  and  1/10  c.c.  of  the  5  per  cent,  emulsion  of  sheep's  red  blood  corpuscles. 

The  tubes  are  well  shaken,  and  the  rack  is  replaced  in  the  incubator  for  from 
10  minutes  to  half-an-hour.  Only  experience  can  enable  one  to  judge  the  correct 
time  at  which  to  read  the  residts,  but,  broadly  speaking,  one  is  safe  in  doing  so 
when  tubes  A,  1,  2,  etc.,  are  completely  haemol^^sed. 

There  must  always  be  complete  haemolysis  in  A,  which  proves  that  the 
complement  is  not  being  fixed  by  the  antigen  alone. 

There  should  always  be  complete  haemolysis  in  tubes  1,  2,  etc.,  which  proves 
that  the  serum  alone  is  not  fixing  complement.  A  few  syphilitic  sera  have  this 
property,  and  they  are,  therefore,  called  amphoteric. 

If  the  reaction  is  positive,  there  should  be  no  haemol3'.sis  in  tubes  lA,  2A,  etc., 
while  if  the  reaction  is  negative,  there  should  be  complete  haemolysis  in  these  tubes. 

Between  haemolysis  and  precipitation  there  are  several  intermediary  stages, 
and  one  can  interpret  these  by  experience  only,  and  by  comparing  the  result  with 
the  clinical  history  of  the  case. 


CHAPTER   X. 

THE  RATIONALE   OR  MODUS  OPERANDI  OF  THE  WASSERMANN 
REACTION  AND  ABDERHALDEN'S  TEST. 

History. 

Bordet  and  Geugou^  were  the  first  actually  to  demoustrate  the  occurrence 
of  an  antibody,  by  means  of  the  complement-fixation  test.  Wassermann  did  much 
work  on  these  lines,  and,  in  conjunction  with  Bruck,-  he  published  several  papers 
referring  to  tuberculosis  and  other  diseases,  from  this  aspect.  Wassermann's  next 
step  was  to  apply  this  test  to  syphilis,  but  he  was  confronted  with  the  difficulty  that 
the  SpirocJiaeia  jMllida  had,  up  to  that  time,  resisted  all  attempts  fo  be  cultured, 
and  so  he  was  forced  to  use  an  extract  of  a  viscus  which  was  rich  in  these  organisms. 
Consequently  an  extract  of  a  foetal  syphilitic  Uver  was  used  as  antigen.  As  such 
an  extract  was  found  to  act  perfectly  well,  Wassermann  and  Bruck^  brought  out 
their  serum  diagnosis  of  syphilis,  which  has  since  gone  by  the  name  of  the  Wasser- 
mann reaction. 

Owing  to  the  labour  entailed  in  carrying  out  the  complement  fixation  test, 
various  workers  attempted  to  supplant  it  by  precipitation  tests.  Fornet  and 
Schereschewsky,*and  Michaelis^  claimed  that  they  got  a  definite  precipitate  by  the 
action  of  a  syphilitic  serum  on  an  extract  containing  a  large  amount  of  syphilitic 
antigen. 

Forges  and  Meier,*  instead  of  using  a  syphihtic  antigen,  employed  a  1  per  cent, 
solution  of  sodium  glycocholate.  Klausner'  merely  diluted  the  sera  with  distilled 
water.  None  of  these  precipitation  tests  was  ultimately  found  to  give  satisfactory 
results.  The  next  step  was  Schiirmann's*  colour  test.  Schiirmann  was  under  the 
impression  that  s)rphilitic  sera  contained  lactic  acid,  and  he  attempted  to  demon-strate 
this  with  UfEelmann's  reagent,  and  later  with  perhydrol  mixed  with  phenol  and 
ferric  chloride.  This  test  was  soon  found  to  be  fallacious.  Assuming  that  the  modus 
operandi  of  the  AVassermann  reaction  depended  on  a  precipitation,  JacobsthaP 
suggested  a  method  which  he  termed  the  "  optic  serodiagnosis  of  syphilis."     The 


70  THE    BIOLOGY,    CLINICAL    ASPECT    AND   TREATMENT   OF   SYPHILIS. 

patient's  serum  is  mixed  with  au  alcoholic  extract  of  syphilitic  liver,  and  the 
resulting  precipitate  is  examined  by  the  dark  ground  illumination  method.  A 
strong  positive  reaction  appears  as  a  clumpy  precipitate,  and  a  negative  reaction 
as  a  thick  emulsion  of  very  fine  particles.  As  Jacobsthal's  observation  throws 
some  light  upon  the  rationale  of  the  Wassermann  reaction,  it  will  be  referred  to 
later. 

As  no  tests  could  be  found  to  supplant  the  reaction,  various  attempts  were 
made  to  simplif)^  the  technique. 

Levaditi  and  Yamanouchi,^"  instead  of  using  immunised  rabbit's  serimi  as 
the  amboceptor  in  the  haemolytic  system,  rehed  upon  the  human  serum  already 
present,  because  human  serum  contains  a  natm'al  amboceptor  to  sheep's  blood. 

The  natural  complement  was  also  used  by  Hecht^^  and  Fleming.^^ 

Laudsteiner,  Miiller  and  PotzF^  next  found  that  an  efficient  antigen  could 
be  prepared  from  tissues  which  had  never  harboured  a  Spirochaeta  jiallida. 

As  both  amboceptor  and  complement  retain  their  active  properties  if  dried, 
measured  quantities  of  these  were  taken  up  by  measured  sizes  of  filter  paper,  dried, 
and  dissolved  in  salme,  when  required.  Modifications  in  the  reaction  were  also 
made,  in  order  to  diminish  the  number  of  negative  results  obtained  in  syphilitic 
cases.  Cholesterol^*  -"  was  added  to  the  antigen,  and  Wechselmann^^  advocated 
shaking  the  sera  beforehand  with  barium  sulphate,  to  precipitate  what  he  called 
"  complementoid  bodies." 

Another  test  which  requires  mention,  as  it  has  some  bearing  upon  the  rationale 
of  the  reaction,  is  the  Meiostagmine  *  reaction  suggested  by  Ascoli,^*  used  by  him. 
as  a  diagnostic  procedure  in  typhoid  fever,  and  apphed  by  Izar^'  to  syphihs.  The 
test  is  a  physico-chemical  reaction  of  immunity,  depending  on  a  change  in  surface 
tension  when  an  antibody  is  brought  in  contact  with  its  own  antigen. 

The  consensus  of  opinion  is,  that  no  test  for  syphilis  is  so  valuable  as  the 
Wassermann  reaction,  and  that  all  modifications  of  the  original  technique  detract 
from  the  reliabihty  of  the  test.  The  attempt  to  sharpen  the  reaction,  by  adding 
cholesterol  to  the  antigen,  has  met  with  great  approval,  although  the  view  that 
non-specific  reactions  are  obtained  is  fast  gaining  ground.  Wechselmann's  method 
has  not  received  much  attention,  but  Lange^^  obtained  good  results  in  a  series  of 
cases  in  which  both  methods  were  simultaneously  performed. 

As  these  modifications  to  sharpen  the  Wassermann  reaction  help  to  explain 
the  rationale  of  it,  a  fuller  description  of  them  will  be  found  later. 

■-■  /jLf'ioiv  (smaller),  (TTd(a  (drop). 


RATIONALE    OF   THE    WASSERMANN   AND   ABDERHALDEN   TESTS.  71 

The  Modus  Operandi  or  Rationale  of  the  Wassermann  Reaction. 
Ill  the  Wasseriuami  reaction  we  are  concerned  with  four  factors  : — 

(1)  Antigen. 

(2)  Complement. 

(3)  Antibody. 

(4)  Haemolytic  system. 

As  the  haemolytic  system  is  common  to  all  complement  fixation  tests,  it  is 
necessary,  at  present,  to  discuss  the  first  three  factors  only.  Moreover,  the  explana- 
tion to  be  given  of  the  )nodus  operandi  of  these  three  factors  will  also  clear  up  the 
rationale  of  the  haemolytic  system,  because  in  both  we  are  dealing  with  an  antigen, 
complement  and  an  antibody. 

Since  the  antigen  need  not  necessarily  be  an  extract  of  syphilitic  material,  the 
reaction  ceases  to  fall  in  line  with  the  bacterial  complement  fixation  tests  originated 
by  Bordet  and  Gengou.^ 

Owing  also  to  the  fact  that  a  positive  Wassermann  reaction  may  be 
obtained  in  conditions  other  than  syphiUtic  ones,  the  reaction  ceases  to  be  a 
specific  reaction. 

Therefore  the  third  factor  ought  not  to  be  called  an  antibody,  since  it  is  in  no 
wise  specific,  hence  it  is  best  called  reacting  substance,  or  Reagin,  for  short. 

Antigen. 

It  is  now  a  well-known  fact  that  one,  if  not  the  main,  principle  in  the  antigen, 
is  a  Upoid,  and  that  the  hpoid  which  has  the  best  action  is  that  in  which  the  ratio 
between  nitrogen  and  phosphorus  is  as  Ni:Pi  (lecithin),  as  demonstrated  by  Thiele 
and  Embleton.^-' 

Although  we  know  that  the  antigen  is  a  Upoid,  this  knowledge  is  of  no  great 
service,  as  the  term  "  lipoid  "  embraces  so  many  substances,  some  of  which  have 
no  antigenic  properties,  and  all  of  which  are  extremely  complex.  Therefore,  there 
must  be  some  active  substance,  or  combmation  of  substances,  in  the  lipoid,  which  is 
primarily  responsible  for  the  antigenic  action.  For  a  substance  to  have  antigenic 
properties,  it  appears  to  be  necessary  for  it  to  contain  nitrogen  in  its  molecule.  The 
nitrogen,  in  the  form  of  amino-acid,  appears  to  be  the  active  part  of  the  hpoid,  since 
artificial  antigens  can  be  prepared,  provided  they  contain  amino-acid  groups.  Tested 
by  Van  Slyke's  method  with  nitrous  acid,  but  without  previous  precipitation  with 


72 


THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF    SYPHILIS. 


alcohol,  the  antigen  which  I  have  always  used  (extract  of  congenital  syphilitic  liver), 
gave  the  following  amino-acid  value  : — 


Vol.  of  Antigen 

diluted  1  in  10  with 

Saline. 

Vol.  of  N. 
collected. 

Vol.  of  N.                Vol.  of  N. 
from  solution.          from  100  c.c. 

Weight  of  N. 
from  100  0.0. 

c.c. 
5 

c.c. 
100 

C.C. 

0-50 

0.0. 

10  00 

mgm. 
11  -70 

Temperature        ...         ...         ...  ...  15°  C. 

Pressure  of  gas     ...         ...         ...  ...  750  mm. 

Weight  of  1  c.c.  of  N.  at  15"  C.  and 

750  mm.            ...         ...         ...  ...  117  mgms. 

If  a  trace  of  formalin  be  added  to  an  antigen,  the  antigenic  properties  are 
increased  ;  and,  at  the  same  time,  the  amino-acid  content  is  decreased  by  about  half. 

Formalin  increases  the  antigen  action,  because  the  replacement  of  the  amino 
groups  by  a  methane  group  increases  the  size  of  the  colloidal  particle — • 

H.COH  +  E.NHj  =  R.N.CH,  +  H.O. 

The  proof  that  the  colloidal  particle  is  increased  in  size  is  shown  by  the  fact 
that  the  R.N.CHj  molecule  requires  about  three  times  as  much  ammonium 
sulphate  to  precipitate  it  as  the  E.NHj  molecule  does. 

Therefore,  although  an  amino  group  is  primarily  responsible  for  the  action  of 
antigen,  it  is  not  wholly  responsible,  since  the  formalised  jsroduct  will  act  as  an 
antigen,  and  this  leads  me  to  the  conclusion  that  the  size  of  the  colloidal  particle 
plays  an  important  part  in  the  reaction. 

Three  c.c.  of  antigen  were  taken,  and  were  divided  into  three  parts.  To  1  c.c. 
1  drop  of  a  40  per  cent,  solution  of  formaUn  was  added  (antigen  B.),  and  to 
another  1  c.c.  1  drop  of  a  1  in  10  of  a  40  per  cent,  solution  of  formalin  was  added 
(antigen  C),  antigen  A  being  the  control. 


Antigen 

Antigen 

Antigen. 

Antigen 

+  Complement 

+  Complement 

+  Complement. 

+  SyphiUtic 

+  Normal 

Serum. 

Serum. 

A.— Iin5      

_ 

+  +  + 

+ 

A.— 1  in  10 

— 

+  +  + 

— 

A.— 1  in  20 

— 

+  +  + 

— 

B.— Iin5      

+  +  + 

+  +  + 

+  +  + 

B.— linlO 

+  + 

+  +  + 

+  +  + 

B.— Iin20 

— 

+  +  + 

+  + 

C— linS       

— 

+  +  + 

+  + 

C— linlO 

— 

+  +  + 

— 

C— lin20 

— 

+  +  + 

— 

RATIONALE    OF   THE    WASSERMANN    AND    ABDERHALDEN   TESTS.  73 

A  few  days  were  allowed  to  elapse  before  the  experiment  was  carried  out,  so 
as  to  be  quite  sure  that  no  free  formalin  was  present  which  might  fix  complement. 
These  same  antigens,  tested  one  week,  and  two  weeks  later,  gave  approximately 
the  same  results.  It  must  be  stated  that  the  antigen  is  neither  specific  nor  absolutely 
necessary  for  the  Wasserniann  reaction. 

As  the  Wassermann  reaction  is  generally  performed,  for  the  fixation  to  be 
complete,  the  tube  must  contain  antigen,  complement,  and  a  serum  containing 
reagin  ;  but  it  occasionally  happens  that  reagin  and  complement  alone  are  sufficient 
to  produce  fixation,  and  to  such  a  phenomeyion  the  term  amphoterism  or  Eigen- 
hemmung  is  given. 

Amphoteric  sera  are  practically  always  syphihtic  sera.  They  are  more 
commonly  met  with  in  late  than  in  early  cases  of  syphilis,  and  occur  not  infrequently 
in  the  cases  of  Ipnphocytomata  of  syphihtic  origin,  although  the  patient  may  no 
longer  be  in  an  active  syphilitic  condition. 

The  amphoterism  is  due  to  an  excess  of  lipoid,  which  is  attached  to  the  globulin 
molecule.  The  more  lipoid  there  is  attached  to  the  globulin  molecule,  the  larger 
is  the  molecule,  and  the  greater  its  adsorptive  capacity.  Therefore,  from  the  few 
remarks  already  made,  it  looks  as  if  the  Wassermann  reaction  was  not  a  specific 
reaction,  but  merely  an  adsorption  or  precipitation  reaction,  depending  partly 
upon  the  size  of  the  lipoid-globulin  (reagin)  molecule. 

Although,  in  my  opinion,  an  extract  of  foetal  syphilitic  tissue  gives  the  best 
results,  there  is  not  very  much  to  choose  between  this  and  an  alcoholic  extract  of 
ordinary,  or,  better,  autolysed  material. 

An  extract  of  spirochaetae  acts  very  indifferently  as  an  antigen,  owing  to  the 
fact  that  the  emulsion  contains  sufficient  free  fatty  acid  or,  what  is  more  probable, 
that  the  parasitic  lipoid-globulin  molecule  contains  an  unsaturated  fatty  acid  group, 
and  that  this  prevents  adsorption.  WTien  it  became  generally  known  that 
the  antigen's  active  principle  was  a  lipoid,  several  observers  manufactured  artificial 
antigens,  and  the  chief  substance  added  was  cholesterol,^*  -"  ^^  although  none 
of  these  observers  appeared  to  have  any  reason  for  adding  this  substance.  At 
the  present  time,  great  differences  of  opinion  prevail  as  to  whether  the  addition 
of  cholesterol  does  not,  in  sharpening  the  reaction  by  reason  of  its  great  adsorptive 
powers,  cause  positive  results  to  be  obtained  with  sera  which  should  have  given 
negative  reactions.  At  first,  cholesterol  antigens  found  great  favour,  but  several 
observers  in  Germany,  France  and  Italy-^  have  recently  given  them  up,  owing  to 
the  fact  that  normal  sera  were  found  to  give  positive  results. 

In  England,  Thiele  and  Embleton^'  have  come  to  the  conclusion  that  the 
addition  of  cholesterol  gives  non-specific  reactions,  and  in  my  research  work  on  the 


74  THE   BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

rationale  of  the  Wassermaun  reaction  I  have  carried  out  several  experiments 
with  cholesterol,  about  which  a  few  remarks  may  be  stated  here. 

Provided  that  the  patient's  serum  is  inactivated  within  forty-eight  hours  of 
its  withdrawal,  and  that  the  serum  is  neither  kept  longer  than  twenty-four  hours 
in  an  ice  incubator,  nor  longer  than  ten  days  at  room  temperature — and  here  the 
time  of  year  plays  a  r6le — the  risk  of  obtaining  a  positive  reaction  in  a  non-syphilitic 
case  is  remote,  but  possible,  when  an  antigen  is  used  which  is  made  up  with  an 
aqueous  solution  of  cholesterol,  and  which  has  been  properly  standardised. 

If,  on  the  other  hand,  the  precautions  mentioned  above  are  not  observed — 
often  they  cannot  be,  and  usually  they  are  not  observed — the  risk  referred  to 
becomes  very  great. 

If  it  be  necessary  to  make  the  reaction  sharper,  there  must  be  grounds  for  so 
doing.  For  diagnosis  the  reaction  should  be  seldom  required.  Failing  diagnosis, 
its  next  use  is  to  regulate  treatment.  Making  the  reaction  sharper  means  the 
administration  of  more  treatment,  until,  in  the  majority  of  early  cases  of  sj'phihs, 
it  is  impossible  to  obtain  a  negative  reaction,  even  two  or  three  years  after  the  most 
vigorous  treatment  has  been  given,  when  cHnically  we  assume  the  patient  to  be 
cured. 

Summing  rip  the  points  which  the  addition  of  cholesterol  brought  to  my 
notice,  it  will  be  seen  that  temperature  has  an  influence  upon  the  reaction,  and 
that  a  serum  is  more  easily  affected  if  it  be  from  a  patient  who  formerly  had  syphilis, 
even  if  he  be  now  cured  of  the  disease.  Consequently,  the  next  series  of  experi- 
ments I  undertook  was  to  gauge  the  influence  temperature  had  upon  sera. 

Effect  of  Temperature. 

All  sera  kept  at  room  temperature,  sooner  or  later,  give  a  positive  reaction. 
A  negative  serum  from  a  patient  who  has  had  syphilis  will  tend  to  become  positive 
earher  than  a  serum  from  a  normal  patient.  No  rule  can  be  laid  down  as  to  when 
sera  become  positive,  as  no  two  require  the  same  time.  I  have  found  a  normal 
serum  to  give  a  positive  reaction  after  it  had  been  kept  four  days,  but  this  is  an 
exception.  If  kept  longer  still,  when  bacterial  action  has  autolysed  the  reagin, 
even  strongly  positive  syphilitic  sera  will  give  negative  reactions. 

If  the  sera  are  diluted  with  saline,  and  then  kept,  they  do  not  tend  to  become 
more  positive  ;  but  syphilitic  sera  may  become  negative,  owing  to  precipitation  of 
the  reagin  molecules.  For  the  same  reason,  neither  antigen  nor  complement  will 
keep  when  diluted.  The  protein  molecules  in  diluted  sera  quickly  become  deionised, 
and  this  results  in  their  precipitation.     If  kept  in  an  ice  incubator,  all  sera  develop 


RATIONALE    OF   THE   WASSERMANN   AND   ABDERHALDEN   TESTS.  75 

reagin  at  a  quicker  rate  than  when  kept  at  room  temperature.  Inactivating 
beforehand  prevents  this,  to  some  degree.  I  have  had  two  cases  in  which  normal 
sera  developed  reagin,  after  having  been  in  an  ice  incubator  for  only  twenty-four 
hours.     The  action  of  heat  also  influences  the  reaction. 

Many  S3'philitic  sera  when  inactivated,  i.e.,  heated  for  half  an  hour  at  57°  C, 
become  negative,  whereas  before  being  heated  they  gave  strong  positive  reactions. 

Heating  sera  for  longer  than  half-an-hour  and  at  a  higher  temperature  than 
57°  C,  causes  them  to  develop  reagin. 

Freezing  Point. 

The  freezing  point  of  sera  was  next  tested,  as  I  thought  that  perhaps  s^^philitic 
sera  might  give  a  different  reading  to  normal  sera,  but  such  was  not  the  case.  All 
that  one  could  say  was  that,  generally  speaking,  the  freezing  points  of  syphilitic 
sera  were  slightly  lower  than  those  of  normal  sera  ;  but  the  differences  were  too 
small  to  allow  one  to  separate  a  normal  from  a  syphihtic  case,  and  even  these  small 
differences  showed  no  regular  variation  when  compared  with  the  degree  of  positivity 
of  the  Wassermann  reaction. 

The  factor  upon  which  the  freezing  point  of  sera  is  dependent  is  the  concentra- 
tion of  the  free  salts.  The  concentration  of  the  free  salts  begins  to  vary  after  the 
sera  have  been  kept  for  twentv-four  hours  ;  hence  no  reading  is  accurate  unless 
it  is  made  before  that  time. 

The  freezing  point  of  normal  sera,  according  to  Rona-^  varies  from  — 0"517°C. 
to  — 0"562°  C.  If  the  sera  are  kept,  after  twenty-four  hours  the  freezing  point 
becomes  lower,  which  suggests  that  the  concentration  of  the  free  salts  increases. 

Sera  which  have  been  tested  for  the  freezing  point  may  be  used  for  the 
Wassermann  reaction  afterwards,  provided  they  are  only  frozen  once,  and  for  as 
short  a  time  as  is  practicable. 

If  the  first  reading  is  inaccurate,  and  another  is  required,  i.e.,  if  the  serum  is 
frozen  twice,  the  second  reading  has  a  tendency  to  be  lower  than  the  first,  and  such 
a  serum  may  have  developed  reagin.  Freezing  sera  for  a  longer  period  than  is 
required  for  ordinarily  reading  the  freezing  point,  will  often  make  a  negative  serum 
give  a  positive  Wassermann  reaction. 

Active  Sera. 

Since  inactivat'on  may  destroy  reagin,  I  have  tested  over  2,000  sera  side  by 
side,  active  and  inactive,  with  the  result  that  a  far  greater  percentage  of  positive 
reactions  were  obtained  in  syphihtic  sera  when  they  were  used  active  ;    a  few 


76  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

syphilitic  sera  reacted  positively  only  when  inactivated  ;  and,  very  occasionally, 
a  normal  serum  gave  a  positive  reaction  in  the  active  condition  (five  cases). 

Theoretically,  it  might  be  imagined  that  if  a  serum  were  used  active,  the 
additional  complement  would  suffice  to  give  a  negative  rather  than  a  positive 
reaction. 

Practically,  that  is  not  the  case,  the  reason  being  that  complement  and  anti- 
body (reagin)  are  the  same  substance  chemically ;  and  since  complement  becomes 
antibody  no  hard  and  fast  Une  can  be  drawn  between  them.  Moreover,  when 
complement  becomes  antibody,  it  often  loses  its  complementary  properties,  for 
frequently  syphiUtic  sera  are  to  be  met  with,  in  which  no  complement  can  be  demon- 
strated. It  may  occasionally  happen  that  a  serum  will  give  a  more  positive 
reaction  when  inactivated  than  when  used  active.  This  is  probably  due  to  the 
fact  that  free  fatty  acid  molecules  exist  in  the  active  serum,  and  that  when  the 
serum  is  heated,  more  fatty  acid  molecules  and,  in  addition,  amino-acid  molecules 
are  also  set  free  from  the  reagin  particle,  and  either  of  them,  if  in  excess,  can  fix 
complement. 

Inactivation  injures  the  reagin  molecule.  The  action  of  reagin,  as  will  be 
later  shown,  is  one  of  adsorption  and  consequent  precipitation.  The  adsorptive 
capacity  of  a  molecule  is  partly  dependent  upon  its  peripheral  atoms,  or,  in  other 
words,  ions.  Therefore,  it  will  at  once  be  seen  that,  so  far  as  the  pure  complement 
fixation  test  is  concerned,  sera  should  always  be  used  active.  The  reagin  molecule, 
when  in  the  active  condition,  is  more  as  it  is  when  in  the  body,  and  the  so-called 
complement  which  is  attached  to  it  only  increases  its  anti-complementary  action, 
and  vanishes  in  the  process. 

Pressure. 

The  next  experiment  was  to  test  the  effect  of  pressures,  both  greater  and  less 
than  that  of  the  atmosphere. 

For  minus  pressure  sera  were  left  for  fortj--eight  hours  under  500  mm.  of  Hg., 
instead  of  760  mm.,  at  10°  C.  For  plus  pressure  sera  were  kept  for  forty-eight 
hours  under  850  mm.  of  Hg.,  instead  of  760  mm.,  at  10°  C.  The  action  of  both 
was  the  same,  so  they  can  be  considered  together. 

Normal  sera  tended  to  develop  reagin,  the  degree  of  fixation  depending,  as  was 
found  throughout  this  work,  upon  how  long  the  sera  had  been  kept,  upon  the 
temperature  at  which  they,  were  kept,  and  upon  whether  the  antigen  contained 
cholesterol  or  not.  Syphilitic  sera  which  gave  a  negative -or  a  weak  positive 
reaction  become  very  positive,  and  those  giving  a  positive  reaction  become 
amphoteric. 


RATIONALE    OF   THE   WASSERMANN   AND    ABDERHALDEN   TESTS.  77 

Neither  a  miuus  nor  a  plus  pressure  was  able  to  convert  an  amphoteric  serum 
into  a  negatively  reacting  serum. 

The  action  of  a  minus  pressure  upon  sera  is  probably  to  increase  the  size  of 
the  colloidal  particles  by  precipitating  them.  The  action  of  a  plus  pressure  upon 
sera  is  probably  to  cause  partial  hydrolysis,  which  would  result  in  there  being  an 
excess  of  amino  and  fatty  acid  molecules.  The  lowering  of  the  surface  tension 
is  more  marked  in  those  sera,  which  have  been  subjected  to  a  minus  pressure,  a 
point  in  favour  of  precipitation  as  against  hydrolysis. 


Wechselmann's  Barium  Suplhate  Modification. 

As  Wechselniann'^5  some  years  ago  had  shown  that  shaking  a  negatively 
reacting  serum  with  barium  sulphate  often  resulted  in  the  sermn  becoming  positive, 
I  tried  a  series  of  experiments  with  this  salt,  and  also  with  kaolin,  Kieselguhr,  silicic 
acid  (Kieselsnure),  and  iron  hydroxide.  Barium  sulphate  is  non-colloidal.  Kaolin 
(HjO,  AljO.,,  2SiOj)  is  only  partially  colloidal.  Kieselguhr  is  practically  SiOj,  and 
therefore  colloidal.  Kieselsi'iure  is  Si(OH)^,  and  therefore  strongly  colloidal,  and  so 
is  iron  hydroxide,  which  is  Fe(OH)o. 

The  more  colloidal  the  body,  the  less  influence  it  had  in  causing  an  alteration 
in  the  reactions,  and  vice  versa. 

Barium  sulphate  tends,  but  shghtly  only,  to  make  normal  sera  positive  ;  time, 
temperature  and  cholesterol  are,  as  usual,  influencing  factors.  Syphilitic  sera  giving 
a  negative  reaction  become  positive  ;  those  giving  a  feeble  positive  reaction  become 
markedly  positive  ;  those  giving  a  positive  reaction  become  amphoteric  ;  while 
primarily  amphoteric  sera  remain  unchanged. 

Kaohn  has  a  similar  action,  but  to  a  much  less  degree.  Kieselguhr  is  feebler 
still,  while  Kieselsdure  and  iron  hydroxide  are  without  action.  Therefore  the  degree 
of  activity  varies  inversely  as  the  colloidal  nature  of  the  body  added. 

Now  comes  the  question  as  to  how  barium  sulphate  acts.  Barium  sulphate 
cannot  carrj^  down  ions,  since  it  is  itself  non-ionisable.  It  can  take  down  some 
fatty  acid,  but  this  alone  would  not  suffice  to  account  for  the  increased  positive 
reaction,  which,  in  some  cases,  is  often  considerable.  Barium  sulphate,  being 
non-colloidal,  no  doubt  increases  the  size  of  the  colloidal  particles,  and  in  this  way 
acts  as  a  very  slight  protein-precipitant.  The  more  vigorously  the  barium  sulphate 
serum  is  shaken,  and  the  longer  the  salt  is  kept  in  contact  with  the  serum,  the  more 
positive  will  the  reaction  be,  as  protein  precipitation  is  increased.  Polarimeter 
readings  carried  out  at  different  intervals  confii-m  this. 


78  THE    BIOLOGY,    CLINICAL  ASPECT   AND   TREATMENT   OF   SYPHILIS. 

To  prove  that  barium  sulphate  acted  by  precipitation,  I  examined  with  the 
stalagmometer  a  series  of  sera,  before  and  after  treatment  with  barium  sulphate. 

The  stalagmometer  measures  the  surface  tension.  The  surface  tension  of  a 
colloidal  solution  is  maintained  by  the  colloidal  particles  in  the  solution.  Hence 
it  will  follow,  that  if  the  colloidal  particles  are  precipitated,  the  surface  tension 
must  be  lowered.  The  barium  sulphate-treated  sera  were  found  to  have  a  slightly 
lower  surface  tension  than  the  plain  sera.  Here  it  may  also  be  stated  that  plain 
syphilitic  sera  cannot  be  differentiated  from  plain  normal  sera  by  measuring  their 
surface  tension. 

Ascoli  and  Izar^^  ^'  showed  that  the  surface  tension  of  syphilitic  sera  was 
lowered  when  antigen  and  complement  were  added  thereto,  but  not  when  the  two 
latter  were  added  to  normal  sera,  a  fact  which  proves  that  the  mixture  of  antigen 
reagin  and  complement  results  in  a  precipitation  of  certain  colloidal  particles,  and 
this  could  not  have  come  about  without  previous  adsorption. 


Reagin. 

The  question  now  arises  as  to  what  reagin  is.  If  my  work  on  the  chemistry 
of  the  Leucocytozoon  syphilidis  be  referred  to'^  '^  ^*  (Chapter  VI),  it  will  be  seen 
that  the  phases  of  the  parasite  are  rich  in  lecithin-globulin,  and  that  the  protoplasm 
of  the  plasma  cells  also  contains  this  substance. 

It  is  a  well-known  fact  that  the  host  protects  itself  with  weapons  of  the  same 
nature  as  those  with  which  it  is  attacked.  It  is,  moreover,  common  knowledge, 
that  protective  substances,  although  originating  in  cells,  do  not  remain  intra- 
cellular ;  they  circulate  in  the  blood,  or,  more  strictly  speaking,  in  the  serum. 

Wassermanu  and  Lange^*  recently  showed  that  the  reagin  substance  in  the 
cerebro-spinal  fluid  came  from  the  cells  which  constituted  the  lymphocytosis.  That 
is  true,  so  far  as  it  goes,  but  it  is  not  only  from  the  lymphocytes  that  the  reagin 
originates — it  also  comes  from  the  epithelial  cells  of  the  choroid  plexuses,  and  from 
the  nerve  cells,  especially  in  the  parenchymatous  nerve  lesions.  The  epithelial  cells 
of  the  choroid  plexuses,  and  Nissl's  granules  are  made  up  of  lipoid-globuHn  adsorption 
complexes.  If  the  reagin  in  the  cerebro-spinal  fluid  comes  from  these  cells,  it  rather 
suggests  that  the  reagin  is  a  Hpoid-globulin.  One  of  the  functions  of  these  lipoid- 
globulins  in  syphihs  is,  as  I  have  shown  elsewhere,-*  ^^  to  carry  oxygen  ferments. 
Now,  the  cerebro-spinal  fluid  in  cases  of  degenerative  encephalitis  is  rich  in  oxydases  ; 
the  epithelial  cells  of  the  choroid  plexuses,  and  Nissl's  granules  give  marked 
oxydase  reactions  ;  therefore,  the  proof  is  strong  that  the  reagin  is  the  same 
substance  as  the  lipoid-globulin  of  certain  cells.     It  becomes  still  stronger,   when 


RATIONALE    OF   THE   WASSERMANN   AXD    ABDERHALDEN   TESTS.  79 

attention  is  called  to  the  fact,  that  the  amount  of  globulin  in  the  cerebro-spinal 
fluid  is  increased  in  cases  of  syphilitic  lesions  of  the  central  nervous  system,  and 
that  this  globulin  is  frequently  to  be  found  in  an  adsorption  complex  with  a  lipoid. 

Thinking  it  highly  feasible,  then,  that  the  reagin  was  lecithin-globulin,  I  next 
tried  a  series  of  experiments  to  find  out  the  action  of  pure  lecithin-globuhn  upon 
complement,  and  then  added  it  to  sera  and  repeated  the  same  experiments  with 
butyric,  palmitic,  stearic  and  oleic  acids,  alone,  with  normal  sera  (human,  and  equine) 
and  with  lecithin-globulin.  Similar  experiments  were  conducted  with  tripalmitin, 
tristearin,  and  triolein,  and  also  with  other  nitrogen  and  phosphorus-containing 
hpoids,  namely,  cerebrin  and  protagon. 

As  very  similar  results  were  obtained,  space  may  be  saved  by  giving  a  general 
statement  of  them. 

The  lecithin-globulin  used  in  these  experiments  was  obtained  from  a  case  of 
pseudo-chyclous  ascites,  and  it  was  kindly  given  to  me  by  Dr.  Mackenzie-Wallis.  A 
saline  emulsion  of  this  lecithin-globuhn  did  not  deviate  compleuient,  and,  when 
added  to  normal  serum,  it  produced  no  change  in  the  reaction.  When  added  ta 
syphiUtic  sera,  in  some  it  made  no  alteration,  in  others  it  either  increased  or  decreased 
the  reaction.  Its  most  usual  effect  was  considerably  to  decrease  the  reaction  in 
all  stages  of  s)'philis  ;  in  fact,  a  serum  amphoteric  under  ordinary  circumstances 
often  gave  a  negative  reaction,  on  the  addition  of  lecithin-globuhn.  In  only  the 
minority  of  instances  was  a  negative  reaction  converted  into  a  positive  one,  and 
the  only  cases  in  which  this  happened  were  those  of  patients  in  the  latent  stage 
of  syphilis. 

The  reason  why  positive  sera  became  negative,  was  probably  because  the  lecithin- 
globulin  emulsion  contained  some  free  fatty  acid,  which,  if  not  too  great  in  amount, 
can  readjust  complement,  or  prevent  adsorption. 

The  reason  why  negative  syphilitic  sera  became  positive  was  probably  because 
the  reagin  contained  free  fatty  acid  groups,  which  primarily  were  responsible 
for  the  negative  reaction,  and  these  free  fatty  acid  groups,  plus  those  contained 
in  the  lecithin-globulin  emulsion,  were  sufficient  to  fix  complement,  since  excess  of 
fatty  acids  has  this  action. 

All  the  fatty  acid  mixtures  had  a  similar  action,  although  they  differed  in 
degree,  the  action  of  oleic  acid  being  the  most  pronounced.  Normal  sera  tended 
to  develop  reagin,  a  phenomenon  dependent  upon  the  length  of  time  during  which 
the  fatty  acid  had  been  in  contact  with  the  serum.  Syphilitic  sera  giving  a  negative 
reaction  usually  became  markedly  positive.  Syphilitic  sera  giving  a  feeble  positive 
reaction  often  became  amphoteric.  Sera  giving  a  strong  positive  reaction,  and 
those  which  were  primarily  amphoteric,  often  became  completely  negative. 

F 


80  THE   BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT    OF    SYPHILIS. 

The  differeut  results  depend,  as  in  the  previous  case,  upon  the  amount  of  free 
fatty  acid  :  if  in  excess,  then  fixation  of  complement ;  if  not  in  excess,  then 
readjustment  of  complement  followed. 

The  fatty  acid  esters  or  triglycerides  had  a  strong  anti-complementary  action, 
and  all  sera  became  positive  or  amphoteric. 

Occasionally,  most  contradictory  and  irregular  results  were  obtained  with  the 
triglycerides,  and  I  found  later  these  results  were  due  to  the  powerful  action  certain 
sera  had  in  breaking  down  the  triglycerides  into  their  corresponding  fatty  acids. 

Cerebrin,  broadly  speaking,  behaved  like  a  fatty  acid,  while  protagon  acted  like 
a  triglyceride.     Both  were  easily  broken  down  into  free  fatty  acids. 

From  the  behaviour  of  the  saline  emulsion  of  lecithin-globuUn  in  the  preceding 
experiment,  doubts  might  be  cast  upon  my  view  that  the  reagin  is  of  a  lecithin- 
globulin  nature. 

Lecithin-globulin  cannot  be  extracted  from  the  fluid  in  which  it  is,  unless  it 
is  precipitated ;  therefore,  in  the  process  of  precipitation,  some  change  may  have 
taken  place  which  would  alter  its  physical  properties.  Precipitated  globuhn  will 
fail  to  give  the  goldsol  reaction,  because,  in  the  process  of  precipitation,  theglobuUn 
has  lost  its  electric  charge,  or,  in  other  words,  has  had  its  ions  detached.  The  same 
is  the  case  with  the  lecithin-globulin.  When  the  lecithin-globulin  is  added  to  a 
normal  serum,  the  reaction  becomes  positive,  which  proves  that  the  hpoid-globuhn 
in  the  serum  has  adsorbed  the  lecithin-globuhn,  with  the  residt  that  its  molecules 
are  increased  in  size,  and  are  made  to  resemble  reagin. 

It  is  only  the  lipoid-globulin  molecule  in  the  serum  which  is  capable  of  forming 
adsorption  complexes ;  therefore,  it  would  appear  that  reagin  is  lipoid-globulin, 
the  molecule  of  which  has  reached  a  certain  size,  and  is  a  molecule  which  is  capable 
of  adsorbing  other  similar  substances,  owing  to  the  ions  which  are  attached  thereto. 

Complement. 

All  we  know  about  complement  is  that  it  quickly  vanishes  when  kept,  that  it 
is  thermolabile,  that  it  can  be  preserved  for  a  jieriod  in  concentrated  salt  solutions, 
that  when  once  destroyed  it  cannot  be  rejuvenated,  that  it  can  be  destroyed  by 
shaking  and  by  continued  centrifuging,  and  that  it  is  probably  a  mixture  of  lipoid 
and  globulin,  as  Dean  had  already  suggested.  To  these,  a  few  more  facts  may 
be  added  : — • 

(1)  That  complement  is  often  better  when  it  has  stood  a  few  hours  than  when 
the  blood  has  been  freshly  drawn. 

(2)  That  giving  the  animal  too  much  anaesthetic  destroys  its  action. 

(3)  That  it  keeps  better  at  room  temperature  than  in  an  ice  incubator. 


RATIONALE    OF   THE    WASSEEMANN   AND    ABDERHALDEN   TESTS.  81 

(4)  That  its  action  is  increased  by  the  preseuce  of  a  trace  of  either  au  amino 
or  of  a  fatty  acid. 

(5)  That  no  protein,  no  aniino-acid,  no  fatty  acid,  no  triglyceride,  no  lipoid, 
uo  salt,  nor  any  combination  thereof  will  restore  destroyed  complement. 

(6)  That  lipoid  solvents  destroy  complement. 

(7)  That  alterations  of  pressure  destroy  complement. 

(8)  That  formalin  destroys  complement. 

"What  light  do  these  facts  throw  upon  the  action  and  being  of  complement  ? 
The  fact  that  it  vanishes  when  kept,  suggests  that  some  alteration  has  taken  place 
in  its  colloidal  particles.  From  analogy  to  what  takes  place  in  the  reagiu  particles, 
it  is  possible  that  the  complement  particle  is  robbed  of  some  of  its  salts.  If  this  is 
correct,  then  a  point  is  gained  in  favour  of  the  complement  molecule  being  an 
adsorptive  molecule. 

That  destruction  on  keei^ing  is  still  more  probably  due  to  the  abstraction  of 
salts,  is  shown  by  the  fact  that  complement  may  be  preserved  in  a  contentrated 
solution  of  sodium  chloride,  and  in  a  1  in  3  solution  of  magnesium  sulphate,  which 
prevents  their  abstraction. 

That  it  is  thermolabile  points  neither  here  nor  there,  since  a  multitude  of 
things  may  be  caused  by  keeping  sera  at  57°  C.  Delicate  ferments  may  be 
destroyed,  the  concentration  of  the  free  salts  may  be  altered,  some  lipoid-globulin 
complexes  may  be  spht  up,  an  alteration  in  the  concentration  of  the  free  fatty  acids 
may  ensue,  etc. 

That"  when  once  destroyed  it  cannot  be  rejuvenated,  favours  the  adsorptive 
molecule  view,  since  there  is  something  vital  in  all  these  hpoid-globuhu  colloidal 
compounds,  as  no  hpoid-globuhn  complex  has  as  yet  been  artificially  prepared. 

That  it  can  be  destroyed  by  shaking,  by  continued  centrifuging,  and  by 
altering  the  pressure  at  which  it  is  kept,  are  all  points  in  favour  of  complement 
being  an  adsorptive  complex,  since  these  measures  are  capable  of  precipitating 
and  hj'drolysing  such  complexes. 

That  complement  is  destroyed  by  giving  the  animal  too  much  anaesthetic, 
throws  additional  hght  upon  its  nature.  Chloroform  ansesthesia  destroys  com- 
plement more  effectually  than  ether  anaesthesia.  Both  chloroform  and  ether 
are  hpoid  solvents,  and  both  have  an  avidity  for  oxygen.  Normal  sera,  when 
withdrawn  while  the  patient  is  under  deep  narcosis,  are  liable  to  give  positive 
Wassermann  reactions,  owing  to  the  fact  that  narcosis  causes  an  excess  of  lipoid 
in  the  serum. ^*  We  know  that  the  lipoids  largely  exist  as  adsorption  complexes 
with  globulin.  Therefore,  the  evidence  grows  that  complement  is  a  lipoid-globulin 
colloidal  molecule. 

f2 


82  THE    BIOLOGY,    CLINICAL   ASPECT   AST)   TREATMENT   OF   SYPHILIS. 

From  what  has  just  been  stated,  it  looks  very  much  as  if  complement  aud 
antibody  are  similar  substances,  and  I  am  of  the  opinion  that  they  are. 

Every  serum  contains  lipoid-globulin  particles,  which  vary  in  size.  In  normal 
sera  these  particles  are,  to  m)-  mind,  complement.  If  the  size  of  these  particles 
be  compared,  it  will  be  found  that  they  are  larger  in  syphilitic  than  in  normal  sera. 
These  particles  are,  to  my  mind,  complement  which  has  increased  the  size  of  its 
colloidal  particles,  so  as  to  carry  more  protective  substances  to  overcome  the 
infection ;  hence  they  become  antibody. 

If  a  lipoid,  such  as  antigen,  is  added  to  a  normal  sermu,  the  ultra-microscopic 
particles  increase  in  size,  as  JacobsthaP  was  the  first  to  demonstrate  ;  in  other 
words,  the  complement  molecule  has  taken  up  a  lipoid,  a  phenomenon  well  known 
in  lipoid-globuhn  complexes. 

The  ultra-microscopic  particles  are  still  further  increased  in  size  if  the  antigen 
is  added  to  a  sj'philitic  serum,  especially  if  the  senmi  be  fresh,  i.e.,  if  it  contain 
complement.  This  signifies  that  the  lipoid-globuHu  in  a  syphilitic  serum  has  a 
greater  adsorptive  capacity  than  that  in  a  normal  serum,  which  would  be  natural 
if  it  were  larger  in  size,  but  it  also  shows  that  the  adsorptive  capacity  is  greater 
if  complement  be  present.  In  other  words,  the  adsorptive  capacity  of  a  lipoid- 
globuhn  complex  is  greatest  when  the  molecules  which  make  up  the  particles  have 
not  been  disturbed. 

While  in  the  body,  the  molecules  are  not  likely  to  be  disturbed  for  long,  since 
the  rapidity  with  which  the  blood  balances  a  change  is  phenomenal.  This  accounts 
for  the  failure  experienced  in  differentiating  normal  from  syphihtic  sera  b}'  testing 
them  when  fresh  for  their  freezing  point,  their  viscosity  and  their  hydrogen-ion 
concentration. 

Soon  after  the  blood  is  drawn,  the  vital  part  of  the  lipoid-globuhn  vanishes, 
and  its  adsorptive  capacity  diminishes. 

The  suggestion  that  complement  is  the  forerunner  of  antibody  does  not  throw 
full  hght  upon  the  active  principle  of  complement. 

Since  the  hpoid-globuhn  complexes  are  vehicles  for  oxydases,  and  since  the 
opinion  has  been  frequently  expressed  that  the  Wassermann  reaction  was  of  a 
ferment  nature,  it  struck  me  that  perhaps  oxydases  played  an  important  role  in 
the  reaction.  If  so,  then  it  could  only  be  the  complement  which  held  the  oxydases, 
because  they  are  destroyed  at  57°  C,  the  temperature  at  which  sera  are  inactivated, 
and  by  alcohol,  with  which  the  antigen  is  prepared. 

Several  points  can  be  brought  forward  in  favour  of  complement  being  the 
ferment  holder,  and  of  the  view  that  the  ferment  is  an  oxydase.  Physical  and 
chemical  factors  which  destroy  ferments  destroy  complement.     Anaesthetics  act 


RATIONALE    OF   THE    WASSERMANN   AND    ABDERHALDEX   TESTS.  83 

ill  virtue  of  their  avidity  for  oxygen,  which  they  get  from  both  the  serum  and  the 
cells.  Complement  gives  oxydase  reactions,  which  disappear  when  complement 
action  vanishes. 

Although  it  is  highly  suggestive  that  complement  action  is  due  to  oxydases, 
no  actual  proof  is  forthcoming,  since  I  have  failed  to  replace  complement  by  other 
oxydase-bearing  substances,  and  all  attempts  at  re-oxygenating  inactivated  com- 
plement have,  so  far,  met  with  no  success. 

Summing  up,  we  see  that  complement  and  antibody  are  the  same.  They  con- 
stitute the  lipoid-globub'u  of  the  serum,  and  the  size  of  the  particle  to  some  extent 
determines  whether  it  is  complement  or  antibody.  Also  that,  probably,  complement 
acts  in  virtue  of  its  oxydases,  the  action  of  which  is  primarily  to  aid  adsorption. 


Further  Proofs  and  Mode  of  Action  of  these  Lipoid-GJlobulin  Complexes. 

From  what  has  just  been  stated,  certain  inferences  may  be  drawn.  My 
biochemical  work^^  ^°  ^-  ^*  ^®  on  the  Leucocytozoon  syphilidis  led  me  to  believe  that 
the  protective  substance,  elaborated  by  the  host  to  overcome  the  parasite,  was 
lipoid-globulin,  which  carried  the  ferments  (oxydases)  which  destroyed  the  parasite. 
Complement  is  also  lipoid-globulin,  to  which  there  is  no  doubt  that  oxygen  ferments 
are  attached.  Complement  is,  then,  the  ever-ready  or  normal  resisting  substance 
of  every  animal,  without  which  the  host  would  doubtless  quickly  succumb  to  any 
disease  by  which  it  might  be  attacked.  So  long  as  complement  remains  complement, 
it  behaves  as  an  oxydase,  but,  when  complement  is  destroyed,  its  oxydase  reactions 
vanish.  Therefore  there  is  some  ground  for  suggesting  that  the  vital  part  of  the 
lipoid-globuhn  (complement)  is  an  oxydase. 

As  the  existing  protective  substance  is  often  not  powerful  enough  to  over- 
come the  parasite,  it  is  only  logical  to  suppose  that  the  host  will  increase 
it  in  some  way. 

Broadly  speaking,  one  of  two  things  happens  when  the  body  is  attacked 
by  organisms :  either  the  polymorphonuclear  leucocytes  or  tjie  mononuclear 
leucocytes  are  increased.  As  we  are  concerned  with  syphihs,  it  will  only  be 
necessary  to  dwell  upon  the  latter,  since  the  former  play  no  part  in  combating 
the  infection. 

At  the  same  time  as  the  mononuclears  increase,  the  protective  substance  in  tlic 
serum  increases.  Sufficient  evidence  has  already  been  produced  to  prove  that,  not 
only  is  this  protective  substance  lipoid-globulin,  but  also  that  it  has  a  cellular 


84  THE   BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   SYPHILIS. 

Complement  has  just  been  shown  to  be  a  lipoid-proteiu,  and  to  be  identical 
with  the  protective  substance,  which  happens,  when  it  is  increased,  to  be  called 
antibody ;  therefore  the  suggestion  at  once  arises  that  complement  has  a  cellular 
origin.  This  I  have  proved  to  be  the  case,  as  an  extract  of  a  lymphatic  gland  will 
act  as  complement. 

The  proofs  I  have  for  the  statement  made,  that  the  colloidal  particles  are  larger 
in  S3^hilitic  than  in  normal  sera,  and  that  their  adsorptive  capacity  is  greater, 
should  now  be  given. 

For  the  colloidal  particles  to  be  larger,  either  one  of  two  things  must  happen  : 
there  must  be  more  protein,  or  the  protein  present  must  be  in  a  less  ionised  con- 
dition, i.e.,  less  colloidal,  more  like  a  precipitated  protein.  That  the  latter  is  not 
the  case  can  easily  be  seen,  since  it  would  be  impossible  for  the  particles  to  act 
as  protective  substances,  unless  they  were  in  a  perfectly  colloidal  condition  and 
electrically  charged. 

To  prove  that  the  protein  was  increased  in  syphilitic  sera,  I  estimated  the  total 
nitrogen,  and  found  that  a  higher  value  could  be  obtained  in  syphilitic  than  in 
normal  sera,  an  observation  which  Folin  had  previously  made.  The  increase  of 
nitrogen  is,  presumably,  not  entirely  protein  nitrogen.  Some  of  it  doubtless 
emanates  from  the  lipoid  which  is  attached  to  the  globulin.  Unfortunately,  an 
accurate  estimation  of  the  lipoid  nitrogen  cannot  be  made,  since  precipitation  of 
the  protein,  by  alcohol  or  mercuric  chloride,  also  results  in  the  carrying  down 
of  the  adsorbed  lipoid.  Moreover,  all  the  lipoid,  while  in  the  adsorbed  condition, 
cannot  be  extracted  with  alcohol  and  ether,  and  any  substance  which  frees  the 
lipoid,  hydrolyses  the  protein  to  which  the  Upoid  is  attached,  with  the  result  that 
amino-acids  are  set  free,  and,  at  the  same  tmie,  the  lipoid  breaks  up,  with  the  result 
that  elementary  nitrogen  is  set  free.  Although  a  method  could  doubtless  be  devised 
to  estimate  the  lipoid  nitrogen,  the  amount  of  lipoid  can  be  better  judged  by  other 
means,  such  as  by  measuring  the  optical  activity,  and  staining  properties  of  the 
colloidal  particles,  etc.  By  employing  these  methods,  it  can  be  sho^^l  that  there 
is  an  excess  of  lipoid-protein  in  syphiHtic  sera  ;  that  this  protein  is  a  globuhn,  since 
lipoids  do  not  form  adsorption  complexes  with  albumin  ;  that  the  lipoid  is  proved 
to  be  in  an  adsorption  complex,  since  it  cannot  be  entirely  removed  by  ether  and 
alcohol,  and  that  the  excess  of  lipoid  is  most  marked  in  the  late  or  so-called  tertiary 
cases  of  syphilis. 

This  increase  of  lipoid  in  late  cases  of  syphihs  may  be  proved  in  the  following 
ways : — 

The  so-called  albuminuria  of  the  generalisation  stage  of  syphilis  may,  as  is  well 
known,  be  very  pronounced,  without  there  being  any  clinical  signs  of  kidney  disease. 


RATIONALE   OF  THE    WASSERMANN   AND    ABDERHALDEN   TESTS.  85 

If  the  uriiie  be  examiued,  it  will  be  found  that  the  protein  is  not  albumin  but 
globulin.  The  globulin  comes  from  the  blood,  and  not  from  the  kidney  cells.  The 
kidney  merely  acts  as  a  filter,  and  is  not  diseased.  Such  a  urine  will  give  a  positive 
Wasserraann  reaction. 

On  further  examination,  no  blood  or  casts  are  demonstrable  in  the  urine.  The 
colloidal  particles  (globulin)  are  neither  so  large,  nor  do  they  exhibit  so  pronounced 
an  optical  activity  as  the  colloidal  particles  obtained  from  a  similar  urine  from  a 
very  late  case  of  syphihs. 

Late  syphiHtic  lesions  dii?er  front  early  syphilitic  lesions,  in  that,  in  the  former, 
the  degeneration  of  the  host's  cells  is  far  greater  than  in  the  latter,  although  the 
number  of  parasites  present  is  overwhehningly  larger  in  the  latter. 

The  degeneration  is  of  a  hpoid  nature.  To  give  two  examples  :  If  the  pyramidal 
cells  of  the  brain  cortex,  from  a  case  of  degenerative  encephalitis,  are  examined, 
it  will  be  found  that  varying  portions  of  the  protoplasm  have  become  finely 
granular,  and  that  they  stain  orange  to  yellow  with  p3'ronin.  If  stained  in 
fresh  sections,  the  granules  stain  violet  with  Nile  blue  sulphate,  and  orange  with 
Sudan  III. 

If  the  aorta  from  a  case  of  syphilitic  aortitis  be  examined,  masses  of  lipoid 
material  are  seen  in  the  walls,  and  this  is  never  the  case  in  an  early  and 
acute  endarteritic  lesion.  For  this  important  observation  I  am  indebted  to  Dr. 
Andrewes.^^ 

Moreover,  this  hpoid  degeneration  is  peculiarly  locaHsed  to  the  area  affected. 
This  excess  of  hpoid  doubtless  accounts  for  the  deficiency  in  calcium  salts  which 
Andrewes  has  observed  in  his  ash  analyses  of  syphihtic  aortae.  This  strongly 
suggests  that  salts  have  made  way  for  lipoids,  as  they  do  in  sera,  when  the  hpoid- 
globulin  molecule  increases  in  size.  This  means,  then,  that  larger  lipoid-globulin 
molecules  exist  in  the  sera  from  late  cases  of  sj'philis,  than  in  those  from  early 
cases.  The  larger  the  molecule,  the  greater  its  anti-complementary  action. 
Hence,  no  relationship  exists  between  the  positivity  of  the  reaction  and  the 
number  of  organisms  present  in  the  host. 

The  Wassermann  reaction  is  stronger  in  late  syphihtic  cases  than  in  early 
ones,  because  there  is  an  excess  of  lipoid. 

As  hpoids  can  easily  have  fatty  acid  molecules  set  free  from  their  particles, 
and  as  fatty  acids  may  increase  the  action  of  complement,  this  is  probably  the 
explanation  of  the  not  infrequent  occurrence  of  negative  Wassermann  reactions  in 
late  cases  of  s^'phihs,  especially  when  the  lesions  are  hmited  to  vessels. 

Bisgaard^^  showed  that,  during  death  agony,  and  for  some  time  after,  the 
total  nitrogen  in  the  cerebro-spinal  fluid  was  increased,  and  that  the  main  excess 


86  THE   BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

was  non-proteiu  nitrogen.  Those  who  have  worked  with  the  AA'assermann  reaction, 
have  long  since  been  aware  that,  even  in  people  who  have  never  had  syphilis,  the 
blood  taken  just  before  death,  or  just  after  death,  is  Uable  to  give  a  positive 
Wassermann  reaction. 

From  these  few  remarks,  it  will  be  seen  that,  although  the  globulin  ma}'  be 
partly  responsible  for  the  reaction,  the  lipoid  is  still  more  so.  This  statement  is 
still  further  proved  by  the  fact  that  neither  the  blood  nor  the  urine  from  a  case  of 
non-syphilitic  functional  albuminuria,  in  which  the  jirotein  in  the  urine  is  globulin 
and  not  albumin,  gives  a  positive  Wassermann  reaction.  The  reason  is  because 
the  globulin  from  such  a  case  has  no  lipoid  attached  to  it,  and  that  it  comes  from 
the  glomeruli  of  the  kidneys  and  is  not  filtered  through  from  the  blood,  therefore 
it  is  in  an  isoelectric  condition. 

Having  proved  that  the  reagin  is  a  lipoid-protein,  it  must  now  be  explained 
how  it  acts. 

Lipoid-proteins  have  large  molecules.  They  can  be  seen  when  examined 
ultra-microscopically,  i.e.,  by  the  dark  groimd  illumination  method.  They  possess, 
moreover,  strong  adsorptive  properties,  and,  by  their  presence,  can  render  soluble 
a  substance  which  is,  under  ordinary  circumstances,  insoluble  in  a  certain  medium. 
Their  adsorptive  capacity  is  partly  dependent  upon,  and  regulated  by  the  ions  and 
other  groups  which  are  attached  to  the  molecules. 

Neither  pure  Upoid-globuUn  nor,  still  less,  pure  globulin  has  a  sufficient  anti- 
complementary action  to  cause  as  strong  a  positive  reaction  as  that  given  by  a 
syphilitic  serum. 

Both  pure  lipoid-globulin  and  pure  globulin  are,  practically  speaking, 
isoelectric.  In  their  preparation,  they  have  been  robbed  of  their  ions,  and  although 
ions  are  necessary  for  the  reaction  they  only  play  a  subordinate  role. 

I  undertook  a  series  of  experiments  with  all  the  salts  that  could  be  supposed 
to  be  found  in  normal  serum,  and  tested  them  in  various  strengths  as  to  their 
anti-complementary  and  haemolytic  actions,  and  tested  their  influence  upoii  the 
Wassermann  reaction  itself. 

Broadl}'  speaking,  all  the  salts  had  a  strong  anti-complementary  action  if  they 
were  used  in  much  stronger  concentrations  than  those  in  which  they  would 
naturally  exist,  while  in  their  approximately  normal  strengths  they  had  neither  an 
anti-complementary  nor  a  haemolytic  action,  nor  did  they  in  any  way  influence 
the  Wassermann  reaction.  Therefore  it  cannot  be  the  ions  themselves  upon  which 
the  action  of  reagin  depends. 

If,  then,  the  adsorptive  capacit}'  of  the  reagin  molecule  is  partly  dependent 
upon  its  ions,  it  might  be  expected  that,  the  larger  the  molecule,  the  greater  the 


RATIONALE    OF   THE    WASSERMANN   AND    ABDERHALDEN   TESTS.  87 

power  with  which  the  ions  are  attached  thereto.  The  following  experiments  proved 
this  to  be  the  case  : — 

Some  lymphatic  glands  were  removed  from  syphilitic  and  normal  patients,  each 
divided  into  two  portions,  dried  and  weighed.  The  first  portion  was  incinerated 
and  the  chlorides  estimated  as  sodium  chloride  in  the  ash. 

The  second  portion  was  thoroughly  extracted  with  alcohol,  the  alcoholic 
extracts  collected,  dried,  weighed  and  the  chloride  content  determined.  The 
residue  of  gland  substance  was  then  submitted  to  dialysis  and  the  chlorides 
estimated  in  the  dialysate. 

The  difference  between  the  two  estimations  gave  the  amount  of  chlorides 
fixed  to  the  proteins  in  the  tissue  under  investigation,  and  this  was  found  to  be 
greater  in  the  syphilitic  than  in  the  normal  glands.  The  larger  the  molecule,  not 
only  the  greater  is  the  power  of  attachment  of  the  ions,  but  also  there  will  be 
more  salts  in  the  ionised  condition.  The  proof  of  this  is  seen  in  the  greater  rapidity 
for  clotting  exhibited  by  syphilitic  sera.  My  friend,  Dr.  Myers, ^^  has  recently 
estimated  the  amount  of  calcium  in  sera,  and,  from  the  experiments  he  has  made, 
there  appears  to  be  an  excess  of  ionised  calcium  salts  in  sjqjhilitic  sera.  These 
last  few  remarks  apply  only  to  the  early  stages  of  syphilis,  because  in  the  late 
stages  the  excess  of  lipoids  causes  a  diminution  of  the  salts.  In  the  so-called 
tertiary  stage,  the  calcium  content  of  the  blood  does  not  vary  much  from  the  normal. 

Those  who  have  followed  the  recent  literature  on  syphilis  will  remember  two 
papers  by  Kaplan,-*  on  the  amino  content  of  syphilitic  sera.  Estimating  the 
amino-acids  by  Van  Slyke's  method,  Kaplan  found  that  the  amino  content  of 
syphilitic  sera  was  less  than  that  of  normal  sera.  Kaplan's  explanation  for  the 
difference  was,  that  the  syphilitic  parasites  required  a  considerable  quantity  of 
amino-acids  for  their  development,  and  that  the  serum  lost  what  they  used. 

Before  stating  the  results  I  obtained  by  Van  Slyke's  method,  it  would  be  as 
well  to  di'aw  attention  to  a  few  points  which  Van  Slyke-'^  himself  pointed  out,  before 
any  interpretation  is  given  of  the  fall  of  amino-acids  in  syphilitic  sera,  as  mentioned 
by  Kaplan. 

In  Van  Slyke's  gasometric  estimation  of  the  primary  aliphatic  amino  nitrogen, 
the  various  kinds  of  amino  derivates  do  not  give  off  their  nitrogen  in  the  same 
time.  The  natural  amino-acids,  i.e.,  the  amino  groups  which  are  attached  to  the 
carboxyl  groups  in  the  a-position,  react  in  five  minutes. 

The  e-amino  groups  in  lysine  require  half  an  hour,  therefore  lysine  is  the  only 
natural  amino  acid  which  requires  more  than  five  minutes. 

Ammonia  and  methylamine  require  1-0-2  hours,  and  urea  requires  8  hours. 
Therefore,  these  substances  can  be  excluded  from  having  any  influence  on  the 


88  THE    BIOLOGY,    CLINICAL  ASPECT   AND    TREATMENT   OF    SYPHILIS. 

results  obtained.  The  same  applies  to  the  amino  groups  in  the  purine  and  pyrimidine 
bodies,  which  require  2-5  hours  before  they  react.  Taking  the  amino-acids 
individually,  Van  Slyke  found  that  glycocoll,  alanine,  valine,  leucine,  phenylalanine, 
tyrosine,  aspararginic  acid,  glutaminic  acid  and  cystine,  which  contain  a-amino 
nitrogen  only,  gave  up  all  their  nitrogen  in  five  minutes. 

Lysine  takes  longer,  because  it  contains  E-amino  groups. 

Although  the  guanidine  bodies  contain  nitrogen  atoms,  the^y  do  not  react. 

Arginine  contains  four  nitrogen  atoms,  but  only  one  reacts,  i.e.,  the  nitrogen 
atom  in  the  a-position. 

The  nitrogen  of  the  indol  ring  in  trj'^ptophane,  and  of  the  pyrrholidine  rings 
in  proline  and  oxyprohne,  and  of  the  imidazole  nucleus  in  histidine,  does  not  react ; 
therefore  tryptophane  reacts  with  only  half  its  nitrogen  atoms,  histidine  with  only 
a  third,  arginine  with  only  a  quarter,  and  proline  and  oxyproline  do  not  react  at  all. 

One  explanation  of  the  diminution  of  amino-acids  in  sypliilitic  sera  might 
easily  be,  that  there  is  a  predominance  of  those  which  do  not  react  with  all  their 
nitrogen.  Therefore  it  w'ould  be  worth  while  to  undertake  a  series  of  experiments  to 
prove  if  there  be  an  excess  of  tryptophane,  histidine  and  arginine  in  syphilitic  sera. 

A  very  important  consideration  which  Kaplan  appears  to  have  overlooked  is: 
How  do  the  amino-acids  exist  in  senun  ?  That  a  few  occur  free,  there  can  be  no 
doubt,  as  a  constant  synthesis  and  analysis  of  the  protein  molecules  is  taking  place  in 
the  serum.  That  more  occur  combined  in  the  protein  molecules  is  also  true,  because, 
as  Eniil  Fischer  said  long  ago,  proteins  are  chains  consisting  of  amino-acid  L'nks. 
It  will  follow  from  this,  that  the  larger  the  protein  molecule,  the  greater  the  nrunber 
of  combined  amino  groups  ;  therefore,  the  larger  the  molecule,  the  smaller  the  number 
of  amino  groups  which  will  react  wuth  nitrous  acid.  Hence  a  ready  explanation 
of  Kaplan's  results  would  be  that  the  amino  nitrogen  is  less  in  syphilitic  than  in 
normal  sera,  because  the  protein  molecule  is  larger  in  the  former  than  the  latter. 

The  proof  that  the  larger  the  protein  molecule,  the  fewer  the  amino-acids  which 
react,  is  forthcoming  from  Van  Slyke's  important  observations  that  natural 
proteins  only  reacted  with  a  trace  of  their  nitrogen,  that  the  albumoses  reacted 
with  more,  and  that  the  polypeptides  reacted  with  practically  all. 

This  proves  that  the  albuinoses  are  degeneration  products  of  proteins,  as  I 
have  already  suggested, ^^  ^*  and  it  confirms  Fischer's  theory  of  the  structure  of 
protein,  w'hich  is  that,  the  smaller  the  molecule,  the  greater  the  quantity  of  nitrogen 
that  exists  in  the  form  of  free  amino-acids. 

In  untreated  cases  of  syphilis  I  found,  as  Kaplan  did,  that  the  free  amino 
content  was  less,  but  I  failed  to  trace  any  direct  ratio  between  the  free  amino 
content  and  the  result  of  the  Wassermann  reaction. 


RATIONALE    OF   THE    WASSERMANN    AND   ABDERHALDEN   TESTS. 


80 


If  the  protein  is  not  precipitated  beforehand  with  alcohol,  I  found  that 
syphilitic  sera,  taken  from  patients  wlio  had  received  no  treatment,  gave  a  smaller 
amino-acid  figure  than  normal  sera.  But  again,  no  direct  ratio  existed  between 
the  amino-acid  content  and  the  result  of  the  Wassermann  reaction.  As  I  was 
more  concerned  with  the  study  of  the  protein  molecule  than  with  the  free  amino- 
acids,  in  the  following  experiments  I  did  not  precipitate  the  protein  with  alcohol, 
before  testing  it  by  Van  Slyke's  method. 

If  the  amino  content  of  sera,  half  of  which  have  been  kept  in  an  ice  incubator, 
half  at  room  temperature,  is  tested,  the  amino  content  may  be  either  raised  or 
diminished.  If  raised,  the  difference  is  only  slight;  while  if  lowered,  the  difference 
is  considerable. 


Serum. 

Vol.  of 
Serum. 

Vol.  of  N. 
CoUected. 

Vol.  of  N. 
from  Serum. 

Vol.  of  N. 
from  100  c.c. 

Serum. 

Weight  of  N. 

(mgras.) 
from  100  c.c. 

Serum. 

1— 

Room  temperature  ... 

Ice  incubator 
2 

Room  temperature  ... 

Ice  incubator 
3— 

Room  temperature  ... 

Ice  incubator 
4— 

Room  temperature  ... 

Ice  incubator 

c.c. 

3 
3 

3 
3 

2 
3 

3 
3 

c.c. 

3-70 
4-40 

3-30 
4-00 

2-70 
2-90 

4-70 
2-90 

c.c. 

1-85 
2-20 

1  -65 
2-00 

1-35 
1-45 

2-35 
1-45 

c.c. 

61-70 
73-30 

55  -00 
66-60 

67-50 
48-30 

78-30 
48-30 

mgms. 

71-40 
84-86 

63-68 
77-20 

78-10 
55-90 

90-65 
55-91 

Temperature 

Pressure  of  gas     ... 

Weight  of  1  c.e.  of  N.  at  19°  C.  and 

747  mm. 


19°  C. 

747  mm. 

1-17  mgms. 


The  fact  that  the  difference  is  great  when  the  amino-acid  content  is  lowered, 
suggests  that  cold  increases  the  size  of  the  colloidal  (protein)  molecule.  Cold 
undoubtedly  increases  reagin  formation,  as  stated  before  ;  therefore,  there  is  still 
more  evidence  that  reagin  depends  upon  the  size  of  the  colloidal  particle. 

The  reason  why  the  amino-acid  content  is  sometimes  increased  in  the  cold, 
is  probably  that  fatty  acids  are  thrown  out  of  combination,  and  that  they  have  the 
power  of  liberating  some  of  the  amino-acids  from  the  protein  molecules. 

Salvarsan  raises  the  amino  content  of    sera,  but  the  Wassermann    reaction 


90 


THE   BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT    OF   SYPHILIS. 


may  be  either  positive  or  negative.     The  rise  begins  almost  immediately  after  the 
injection  has  been  given,  and  may  persist  for  some  weeks. 


Vol.  of  Serum. 

Vol.  of  N. 
Collected. 

Vol.  of  N. 
from  Serum. 

Vol.  of  N. 
from  100  c.c. 

Weight  of  N. 

(mgms.) 
from  100  c.c. 

Serum  before  "  006  "— 

2         

Serum  one  hour  after  "  606  "— 

3         

c.c. 
2-25 
3-45 

c.c. 

112 

1-72 

c.c. 
56-25 
57-50 

mgms. 
65-80 
67-25 

Temperature        15°  C. 

Pressure  of  gas     ...         ...         ...         ...  750  mm. 

Weight  of  1  c.c.  of  N.  at  15^  C.  and 

750  mm.  1 -17  mgms 

The  addition  of  fatty  acids  to  sera  increases  the  amino  content,  especially 
the  addition  of  oleic  acid,  which  may  increase  it  sevenfold.  Triglycerides,  on  the 
other  hand,  considerably  depress  it. 

Triglyceride  emulsions  in  sera  give  very  marked  positive  Wassermann 
reactions,  but  fatty  acid  emulsions  may  also  exhibit  a  strong  anti-complementary 
action. 


Serum  (Horse). 


jVol.  of  Serum. 


Vol.  of  N. 
Collected. 


Vol.  of  N. 
from  Serum. 


Vol.  of  N. 

from  100  c.c. 

Serum. 


Weight  of  N. 

from  100  c.c. 

Serum. 


c.c. 

c.c. 

c.c 

c.c. 

mgm. 

I.  Stearic  acid 

1 

0-6 

0-3 

30 

35-37 

II.  Triolein 

2 

0-2 

0-1 

5 

5-89 

III.  Oleic  acid 

2 

2-4 

1-2 

CO 

70-74 

IV.  Normal 

2 

0-4 

0-2 

10 

11-79 

V.  Protagon 

2 

0-2 

0-1 

5 

5 -89 

VI.  Tristearin 

2 

0-2 

0-1 

5 

5-89 

VII.  Cerebrin 

1 

0-4 

0-2 

20 

23-58 

Temperature        14°  C. 

Barometer  ...         ...         ...         ...  763  mm. 

Pressure  of  gas     ...         ...         ...         ...  751mm. 

Weight  of  1  c.c.  of  N.  at  14°  and  751  mm.  1  -179  mgms. 

The  explanation  of  the  fact  that  fatty  acids  increase,  and  triglycerides  decrease 
the  amino-acid  content,  is  that  the  amino-acids  are  amphoteric,  i.e.,  that  they 
dissociate  in  an  aqueous  solution  both  as  bases  and  as  acids. 


EATIONALE    OF   THE   WASSERMANN   AND   ABDERHALDEN  TESTS. 


91 


This  would  make  their  acid  power  very  wealv,  aud  most  possibly  the  fatty 
acids — weak  as  they  are — relatively  stronger.  This  being  so,  the  stronger  acids  would 
tend  to  replace  the  weaker,  so  that  the  amino-acids  would  be  liberated  from  their 
compounds,  just  as,  for  example,  hydrochloric  acid  would,  with  a  sidphite,  form 
a  chloride  and  liberate  sulphurous  acid. 

The  triglycerides,  being  condensation  products  of  glycerol  and  the  fatty  acids, 
would  have  no  acid  power,  and  would  not  displace  the  amiuo-acid  from  their 
compounds. 

Bariiun  sulphate  raises  the  amino  content,  but  this  may  be  due  to  the  air 
which  gets  into  the  sera. 


Serum  (Horse) 

Treated  with  Barium 

Sulphate. 


Vol.  of  Serum. 


Vol.   of  X. 
Collected. 


Vol.  of  N. 
from  Serum. 


Vol.  of  N.    I  Weight  of  N. 
per  100  c.c.    from  100  c.c. 
Serum.  Serum. 


c.c. 

c.c. 

c.c. 

c.c 

mgm. 

I.  Stearic  acid 

1 

1-2 

0-6 

60  0 

68-7 

II.  Trlein       

2 

3-2 

1-6 

80  0 

91-6 

III.  Oleic  acid 

2 

1-9 

0-95 

47-5 

54-39 

IV.  Normal 

2 

2  -2 

11 

55  0 

62-97 

V.  Protagon 

2 

2-2 

11 

55  0 

62-97 

VI.  Tristearin 

2 

1-4 

0-7 

35-0 

40-07 

VII.  Cerebrin 

o 

1-6 

0-8 

40  0 

45-8 

Formalin  markedly  increases  the  amino  content,  and  all  sera  which  have  been 
treated  with  formalin  have  a  very  strong  anti-complementary  action. 


Vol  of  N 

Weight  of  N. 

Vol.  of  Serum. 

! 

Vol.  of  N. 

Vol.  of  N. 
from  Seruiu. 

from  100  c.c. 
Serum. 

(mgms.) 

from  100  c.c. 

Serum. 

c.c. 

c.c. 

c.c. 

c.c. 

mgms. 

Serum  A  alone 3 

2-90 

1-45 

48-30 

56-10 

Serum  A  treated  with 

formalin  (1  drop  40  j 

per  cent,  solution  to  I 

1  c.c.  serum)...         ...              3 

1-80 

0-90 

30-00 

34-80 

Serum  B  alone 3 

4-00 

2-00 

66-60 

77-30 

Serum  B  treated  with  '• 

formahn        2 

1-30 

0-65 

32-70 

37-90 

Temperature 
Pressure  of  gas     . . . 
Weight    of    1    cc. 
738  mm. 


N.    at    16°   C.  and 


16°  C. 

738  ram. 

1  -16  mgms. 


92  THE   BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

From  these  few  remarks,  it  will  be  seen  that  there  is  no  direct  ratio  between 
the  amino  content  of  the  serum  and  the  result  of  the  Wassermann  reaction. 

The  decrease  of  amino  nitrogen  in  syphilitic  sera,  as  shown  in  Van  Slyke's 
method,  is  largely  owing  to  the  fact  that  the  amino-acids  are  more  combined  or 
adsorbed  in  syphilitic,  than  in  normal  sera.  It  does  not  mean  that  there  are  fewer 
amino-acids  in  syphihtic  sera,  since,  if  such  sera  are  hydrolysed,  an  increase  of  amino 
nitrogen  is  obtained  in  syphihtic  sera. 

There  is  an  increase  of  globulin  complexes  in  syphilitic  sera,  which  means 
that  the  protein  molecules  are  bigger,  hence  the  explanation  for  the  diminished 
amino  nitrogen  content. 

It  is  interesting  here  to  note  the  influence  which  the  addition  of  amino-acids 
to  sera  had  upon  the  Wassermann  reaction.  The  results  of  adding  amino-acids 
dissolved  in  sahne  to  sera,  gave  some  important  and  interesting  results.  The  three 
used  were  tyi'osine,  leucine,  and  glycocoll,  in  the  strengths  of  1  in  1,000,  1  in  10,000, 
1  in  100,000  and  1  in  1,000,000.  The  stronger  solutions  had  an  anti-complementary 
action,  and  therefore  tended  to  make  normal  sera  positive.  Some  sera  rich  in 
reagin  became  negative.  The  weak  dilutions  increased  the  action  of  complement, 
and  caused  positive  sera  to  become  negative  ;  glycocoll  had  the  strongest  action 
in  tliis  respect. 

If  the  amino-acids  are,  on  the  other  hand,  dissolved  in  sera,  quite  different 
results  are  obtained.  The  tendency  is  for  all  the  sera  to  become  very  positive. 
Should  a  positive  serum  containing  an  amino-acid  (O'OOl  per  cent.)  be  added  to 
another  serum,  the  reaction  is  less  positive  in  the  mixture  of  the  sera,  one  of  which 
contains  the  amino-acid,  than  in  a  mixture  of  the  same  two  sera,  to  neither  of  which 
an  amino-acid  had  been  added,  and  this  shows  that  some  of  the  acid  has  become 
adsorbed  by  the  lipoid-protein  molecules  of  the  serum  containing  no  amino-acid, 
and  therefore  there  was  less  to  fix  the  complement. 

If  a  free  fatty  acid  be  present  in  addition,  the  activity  of  the  amino-acid  is 
markedly  increased,  and  a  negative  reaction  is  the  result.  A  stearic  acid  s^um, 
giving  &  +  +  -^  +  reaction,  when  mixed  in  equal  parts  with  a  glycocoll  serum 
giving  a  -I-  +  +  reaction,  gives  a  negative  result. 

Fatty  acids  in  excess  have  an  anti-complementary  action  ;  in  weak  dilutions, 
they  appear  to  aid  complement. 

Fatty  acids  frequently  cause  positive  sera  to  become  negative,  but  if  they  have 
been  previously  added  to  normal  sera,  and  the  fatty  acid  normal  sera  are  mixed 
with  the  positive  sera,  the  reaction  usually  remains  positive,  which  points  to  the 
fact  that  normal  sera  can  adsorb  fatty  acids.  Normal  sera  may  give  positive 
reactions  on  the  addition  of  fattv  acids,  as  they  did  with  amino-acids. 


RATIONALE    OF   THE    WASSERMANN   AND   ABDERHALDEN   TESTS.  93 

Triglj'cerides  increase  the  reagin  all  round,  and  always  give  rise  to  a  positive 
reaction.  When  in  sera,  they  are  liable  to  become  split  np  into  fatty  acids.  This 
splitting  up  must  be  borne  in  mind,  since  just  sufficient  fatty  acid  may  be  split  off 
to  make  the  reaction  negative. 

From  these  experiments,  the  influence  of  salvarsau  upon  the  Wassermanu 
reaction  can  be  explained. 

Salvarsan  increases  the  amino  content  of  syphihtic  sera,  and  this  suggests 
that  it  breaks  up  the  lipoid-globuhn  (reagin)  molecule,  a  suggestion  which  is 
supported  by  the  fact  that  salvarsan  decreases  the  clotting  time  of  sera  ;  and 
this  would  be  the  case  if  the  calcium  salts  were  split  off  from  the  lipoid-globulin 
molecules,  thereby  diminishing  their  ionic  action. 

If  the  molecules  are  rendered  smaller,  it  would  at  first  sight  appear  that  the 
Wassermann  reaction  after  salvarsan  would  always  be  negative,  which  is  not  the 
case,  at  any  rate  in  earl}'-  syphihs. 

If  a  syphilitic  plasmoma  be  examined  histologically  before  and  after  salvarsan 
treatment,  it  will  be  noticed  that  the  protoplasm  of  the  plasma  cells  in  the  latter 
case  is  completely  broken  up,  but  each  fragment  still  retains  its  chemical  and 
physical  properties.  If  the  protoplasm  is  broken  up,  the  area  over  which  it  can  act 
is  greater  than  w'hen  the  masses  are  crowded  together.  Therefore,  it  would  appear 
to  be  an  advantage  to  break  up  the  reagin  particles.  Because  they  are  broken 
up,  it  does  not  necessarily  follow  that  each  smaller  particle  does  not  possess  the 
properties  of  lipoid-globulin.  It  is  only  after  several  injections  that  actual 
hydrolysis  occurs,  i.e.,  that  the  hpoid  fraction  is  split  up  into  fatty  acids,  and  the 
globulin  fraction  into  amino-acids. 

So  long  as  the  reagin  particles  are  hpoid-globuUn,  they  will  retain  their 
adsorptive  capacity  ;  and  as  the  area  over  which  they  act  is  greater,  it  follows  that 
the  total  action  will  be  increased,  i.e.,  that  more  complement  will  be  fixed,  and  that 
the  Wassermann  reaction  will  be  more  marked. 

As  I  pointed  out  two  years  ago,^^  it  is  only  after  the  first  two  or  three  injections 
of  salvarsan  that  the  Wassermann  reaction  becomes  more  positive,  and  then, 
after  the  subsecjuent  injections,  it  gradually  diminishes,  until  it  becomes  negative. 

Salvarsau  at  first  increases  the  adsorptive  capacity  of  the  reagin  molecule  by 
breaking  it  up,  and  then  decreases  it  by  causing  hydrolysis. 

That  such  an  explanation  is  probably  correct,  is  shown  by  the  fact  that  the 
increase  of  the  free  amino-acid  content  of  the  serum  is  most  marked,  not  after  the 
first  three  injections  of  salvarsan,  but  after  the  later  injections. 

Often  a  positively  reacting  serum — and  this  is  especially  the  case  in  the 
so-called  tertiary  stage — wiU  become  negative  after  an  injection  of  salvarsan. 


94  THE   BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   SYPHILIS. 

In  the  late  cases  of  syphilis,  the  lipoid  portion  of  the  lipoid-globulin  molecule 
is  greater  than  it  is  in  the  early  cases,  and,  the  larger  the  lipoid  fraction,  the  greater 
the  ease  with  which  an  unsatisfied  fatty  acid  molecule  is  set  free. 

As  stated  before,  a  trace  of  a  free  fatty  acid  will  prevent  adsorption  ;  an  excess 
will  fix  complement.  Therefore,  the  first  action  which  salvarsan  has  in  such  cases, 
is  to  set  free  just  sufficient  fatty  acid  from  the  reagin  molecule  to  readjust 
complement. 

Further  injections  split  up  the  large  hpoid-globuhn  molecules  into  smaller 
ones,  with  the  residt  that  the  reaction  will  be  more  positive  ;  and  finally  hydrolysis 
occurs,  when  the  reaction  becomes  negative.  Therefore  it  at  once  becomes  evident 
that  a  negative  Wassermann  reaction  after  treatment  can  be  no  indication  as 
to  the  number  of  parasites  killed,  or  as  to  whether  any  are  left  behind  or  not.  The 
question  which  now  arises  is,  whether  there  is  any  specificity  in  the  reagin  molecule, 
or  whether  its  action  depends  entirely  upon  physical  conditions  which  are  naturally 
present  in  syphilis,  but  which,  when  brought  into  play  outside  the  body,  can  make 
a  normal  serum  give  a  positive  Wassermann  reaction. 

The  mere  fact  that  an  antigen  is  not  absolutely  necessary,  at  once  rules  out 
the  Wassermann  reaction  as  being  a  specific  reaction,  but  from  this  it  does  not 
necessarily  follow  that  the  reagin  molecule,  when  in  the  body,  has  no  specific 
action.  Further  hght  can  be  thrown  upon  this  point  if  Abderhalden's  test 
is  considered  for  a  moment.  The  serum  of  a  pregnant  woman  will  break  down 
placental  extract — according  to  Abderhalden^' — owing  to  the  i^resence  of  a 
specific  proteolytic  ferment  in  the  serum.  It  will  necessarily  follow  that  the 
placental  extract,  for  the  sera  of  pregnant  women,  will  also  be  specific.  From  this 
it  follows  that  specificity  can  lie  in  the  peptones,  polypeptides,  amino-acids  and 
amines.  There  is  a  hmit  to  the  number  of  these  substances,  but  there  is  no  limit 
to  specificity.  There  is  also  no  hmit  to  the  variation  of  the  physical  configurations 
of  the  molecules  of  the  above  substances,  although  there  is  a  limit  to  their  chemical 
molecular  configurations.  Therefore  there  would  appear  to  be  some  relationship 
between  specificity  and  the  physical  configuration  of  the  foundation  molecule,  upon 
which  are  built  up  the  other  atoms  wliich  go  to  constitute  the  protein  molecule. 

Hence  a  physical  homology  exists  between  the  molecules  of  the  serum  and 
those  of  the  placental  extract. 

For  the  serum  of  a  pregnant  woman  to  break  down  placental  extract,  it  is 
necessary  that  the  serum  should  be  fresh,  or,  in  other  words,  should  contain 
complement. 

Interpreted,  this  means  that  a  serum  cannot  break  down  its  specific  antigen, 
unless  its  molecules  are  ionised,  and  have  oxydases  attached  to  them. 


RATIONALE   OF  THE    VVASSERMANN   AND    ABDERHALDEN   TESTS.  95 

In  the  preceding  pages,  it  was  shown  that  complement  was  lipoid-globulin, 
therefore  it  is  the  lipoid-globulin  molecules  in  the  sera  of  pregnant  women  which 
break  down  the  placental  extract.  Hence  an  analogy  exists  between  these 
molecules  and  the  reagin  molecules  in  syphilitic  sera. 

I  have  already  shown  that  the  action  of  reagin  is  one  of  adsorption.  Therefore, 
on  the  same  principles,  there  is  no  reason  why  adsorption  should  not  take  place 
between  the  lipoid-globulin  particles  of  the  sera  of  pregnant  women  and  those  of 
the  placental  extract. 

Reagin  adsorbs  complement  because  both  have  the  same  physical  molecular 
configuration.  Reagin  will  only  adsorb  an  antigen  which  contains  amino-acid 
atoms,  since  a  variation  in  physical  configuration  of  molecules  can  only  affect  those 
of  proteins,  or  those  upon  which  proteins  are  built  up. 

Adsorption  of  homologous  molecules  results  in  precipitation,  and  further 
dialysis  results  in  hydrolysis.  If  complement  be  dialysed,  its  action  is  destroyed  ; 
and  it  is  so,  too,  with  reagin,  owing  to  the  fact  that  the  lipoid-globulin  molecules 
spUt  up.  In  Abderhalden's  test,  my  view  is  that,  adsorption  between  homologous 
molecules  takes  place,  and  this  results  in  their  precipitation  and  subsequent 
hydrolysis  owing  to  dialysation,  which  allows  sufficient  amino-acid  to  get  through 
the  fish  bladder  to  give  a  positive  ninhydrin  reaction. 

At  first  sight,  it  looks  as  if  Abderhalden's  test  is  specific,  but  not  infrequently 
a  syphihtic  sermn  from  a  non-pregnant  woman  will,  with  placental  extract,  give 
a  positive  ninhydrin  reaction.  Therefore,  as  a  test,  it  can  be  no  more  specific  than 
the  Wassermann  reaction. 

The  fact  that  a  syphilitic  serum  will  give  a  positive  ninhydrin  reaction  with 
placental  extract,  to  my  mind,  throws  a  great  deal  of  hght  upon  both  the  Abderhalden 
and  Wassermann  reactions.  There  is  a  close  similarity  between  the  sera  of 
pregnant  women  and  syphilitic  women,  because  pregnant  women  seem  to  be  very 
httle  affected  by — and  some  even  to  be  immune  from — syphihtic  symptoms. 
Unfortunately,  syphilitic  sera  will  give  a  positive  ninhydrin  reaction,  with  an 
extract  of  ahnost  any  organ.  Therefore  it  looks  very  much  as  if  neither  of  these 
two  reactions  is  specific,  but  that  they  are  merely  group  reactions,  which  depends 
upon  certain  physical  conditions  of  the  protein  molecules,  and  do  not  necessarily 
simulate  the  processes  which  take  place  in  the  body. 

There  is  a  marked  analogy  between  the  interchange  of  action  between  antigen, 
antibody  and  complement,  and  the  interchange  of  action  between  sheep's  red 
blood  corpuscles,  amboceptor  and  complement  (haemolytic  system).  Therefore 
there  must  be  an  analogy  between  the  modus  operandi  of  Abderhalden's  test  and  of 
the  haemolji:ic  system. 


96  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF    SYPHILIS. 

That  haemoglobin  becomes  free,  when  complement  and  a  specific  amboceptor 
is  present,  is  no  proof  that  the  red  blood  corpuscles  have  been  broken  down  by 
proteolytic  ferments  ;  it  is  only  a  proof  that  the  colloidal  membrane  has  been 
altered  by  the  abstraction  of  certain  chemical  groups  attached  to  it,  and  therefore 
rendered  more  pervious  by  an  alteration  of  the  osmotic  pressure.  Syphilitic  sera 
without  any  extract  at  all,  provided  complement  be  present,  will  sometimes  give 
a  positive  ninhydi-iu  reaction,  which  can  be  explained  in  this  way  :  complement 
may  be  fbced  by  reagin  in  the  Wassermann  reaction,  without  there  being  any 
antigen  present.  Owing  to  the  fact  that  the  reagin  and  complement  molecules  are 
homologous,  adsorption  results,  and  then  precipitation.  Precipitated  complement 
is  not  necessarily  destroyed.  A  ratio  exists  between  the  degree  of  precipitation 
and  the  loss  of  action,  since,  if  the  precipitation  be  only  slight,  the  complement 
can  be  collected,  and  its  action  proved  by  placing  it  in  a  haemolytic  system. 

Should,  on  the  other  hand,  the  complement  be  precipitated  in  a  dialysing 
apparatus,  hydrolysis  of  both  the  complement  and  the  precipitating  substance  (reagin) 
takes  place,  with  the  result  that  an  excess  of  amino  atoms  is  formed,  and  it  dialyses 
through  the  fish  bladder,  and  gives  a  positive  ninhydrin  reaction.  Therefore,  in  the 
Wassermann  reaction,  we  are  dealing  with  a  pure  precipitation,  and  in  Abderhalden's 
test,  with  precipitation  and  h)'drolysis. 

The  proofs  for  the  statements  just  made  are  to  be  found  in  the  following 
experiments  :— 

Colloidal  solutions  have  a  surface  tension  which  decreases,  if  the  colloidal 
particles  are  precipitated.  If  normal  sera  are  mixed  with  antigen  and  complement, 
and  then  tested  with  the  stalagmometer,  there  is  no  diminution  in  the  surface  tension. 
If  syphihtic  sera  are  treated  in  the  same  way,  there  is  a  diminution  of  surface  tension, 
and  this  proves  that  when  reagin,  antigen,  and  complement  are  mixed,  a  precipita- 
tion occurs,  or,  in  other  words,  the  solution  in  which  they  are  present  becomes  less 
colloidal. 

From  the  above  it  would  appear,  that  there  is  some  relationship  between  Surface 
tension  and  the  Wassermann  reaction  ;  that  such  is  really  the  case  is  proved  by 
the  fact  that  the  surface  tension  of  sera  is  lowered  by  the  addition  of  barium 
sulphate,  Kieselguhr  and  formalin,  all  of  which  increase  the  anti-complementary 
action  of  sera.  The  addition  of  silicic  acid  or  iron  hydroxide  to  sera  does  not  lower 
the  surface  tension,  and  does  not  cause  sera  to  give  a  positive  Wassermann 
reaction. 

Therefore  there  is  strong  evidence  in  favour  of  the  precipitation  theory  for 
the  Wassermann  reaction.  The  proof  that  Abderhalden's  test  is  primarily  a 
precipitation,  and  finally  a  hydrolysis,  is  shown  by  the  fact  that,  if  fresh  syphilitic 


RATIONALE   OF   THE    WASSERMANN    AND    ABDERHALDEN   TESTS.  97 

sera  are  dialysed,  the  reagin  is  partly  destroyed,  and  the  complement  is  completely 
destroyed. 

Summary. 

It  will  be  seen  from  what  has  been  stated,  that  once  a  serum  has  had  its 
adsorptive  capacity  increased,  as  occurs  to  the  lipoid-globulin  molecules  (reagin) 
in  a  syphihtic  case,  it  is  always  liable  to  exhibit  the  same  phenomenon,  should 
circumstances  arise  which  give  it  the  opportunity. 

Most  of  these  opportunities  arise  only  after  the  blood  has  been  withdrawn. 
Moreover  it  will  be  seen  that  several  factors  may  be  responsible  for  a  positive 
reaction.  An  increase  in  the  size  of  the  protein  molecule,  an  excess  of  hpoid  over 
the  protein,  a  breaking  down  of  the  large  lipoid-globuUn  molecule  into  several 
smaller  ones,  and  an  excess  of  fatty  acids  and  amino-acids.  These  various  factors 
may  be  at  work  without  the  observer's  knowledge,  and  they  cannot  be  prevented 
or  differentiated ;  therefore,  it  must  be  v\Tong  to  state  that  a  positive  Wassermann 
reaction  is  necessarily  indicative  of  active  sypliilis. 

Since  a  free  amino  group,  or  a  free  fatty  acid  group,  can  prevent  what  would 
have  been  a  positively  reacting  serum  from  giving  a  positive  reaction,  it  can  be 
easily  understood,  that  a  negative  reaction  can  neither  exclude  syphilis,  nor  be 
taken  as  an  indication  of  a  cure. 

It  must  be  obviously  incorrect  to  say  that  a  positive  Wassermann  reaction 
means  that  there  are  spirochaetae  in  the  body,  because,  if  true,  a  ratio  would  exist 
between  the  positivity  of  the  reaction  and  the  number  of  spirochaetae  present. 
This  is  by  no  means  the  case,  since  the  most  positive  reactions  are  obtained  from 
those  patients  who  are  suffering  from  diseases  caused  by  syphihs,  such  as  the  inter- 
mediary cutaneous  and  visceral  lymphocytomata  in  which  no  parasites  are 
present,  and  then  in  late  cases  in  which  only  a  few  parasites  are  present. 

The  fact  that  one  may  obtain  a  very  strong  positive  Wassermann  reaction  in 
a  case  of  cutaneous  IjTiiphocytoma  occurring  in  a  patient  who  has  had  syphihs, 
but  is,  as  far  as  one  can  tell,  cured,  throws,  to  my  mind,  a  great  deal  of  light  upon 
the  aetiology  of  certain  chronic  dermatoses,  and  even  on  that  of  malignant  disease 
itself.  

Once  the  body  has  had  to  form  protective  substances,  should  the  call  upon 
them  have  been  a  prolonged  one,  in  many  instances,  in  spite  of  the  fact  that  the 
attacking  force  has  vanished,  the  body  still  goes  on  forming  these  protective  sub- 
stances, and  in  an  ever-increasing  degree,  until  the  protective  substances  them- 
selves become  parasitic,  so  to  speak,  upon  the  host  that  formed  them. 

In  the  case  of  syphilis,  the  protective  substances  are  Upoid-globulin  complexes 

G  2 


98  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF    SYPHILIS. 

which  emanate  from  the  lymphocytes.  The  production  of  these  substances  can 
go  on,  in  spite  of  the  fact  that  there  are  no  more  organisms  to  vanquish,  and  in 
an  ever-increasing  rate,  until  the  lymphocytes  are  strained  to  their  utmost  to  furnish 
these  substances,  and,  in  their  efiorts,  they  become  malignant. 

It  looks  to  me  as  if  there  is  no  one  cause  of  the  leucaemic  and  aleucaemic 
lymphocytoniata^®  and  mahgnant  disease,  but  that  they  are  the  results  of  the 
host's  own  protection  against  parasites,  etc.,  of  which  the  Leucocytozoon  sijpMlidis 
is  one. 

Still  further  proof  in  this  direction  is  the  degree  of  positivity  which  is  not 
infrequently  witnessed  in  sera,  taken  post-mortem.  As  oxydases  are  quickly 
destroyed  post-mortem,  and  as  the  sera  of  some  of  the  late  cases  of  syjihilis  fail  to 
give  oxydase  reactions,  no  ratio  can  exist  between  the  positivity  of  the  reaction 
and  the  oxydase  content.  Therefore,  a  strongly  positive  reaction  need  not  neces- 
sarily signify  that  a  grave  or  widespread  active  syphilitic  condition  exists.  What 
applies  to  the  Wassermann  reaction,  in  my  opinion,  applies  to  Abderhalden's 
test.  It  is  not  tlie  lipoid-glolnilin  itself  which  is  primarily  responsible  for  the 
breaking  down  of  the  organ.  The  active  agent  is  the  oxydase  contained  in  the 
complement,  which  is  necessary  for  the  reaction,  and  is  linked  to  the  hpoid- 
globulin,  which  itself  may  have  a  specific  configuration.  Furthermore,  there  is  no 
evidence  that  the  breaking  do-rni  of  the  organ  is  due  to  a  proteolvtic  or  peptolytic 
ferment.  I  should  not  be  at  all  surprised  if  in  time  all  ferments  are  found  to  be 
oxydases,  and  that  the  differences  in  action  rest  in  the  stereo-chemical  molecular 
configuration  of  the  radicles  to  which  the  oxydases  are  attached  by  means  of  the 
ions. 

The  above  points  to  the  fact  that  the  complement  is  the  most  important  factor 
in  the  reaction;  therefore,  any  modification  which  rehes  upon  the  patient's  own 
complement  must  be  fallacious,  as  the  action  of  the  complement  is  altered  by  the 
behaviour  of  the  radicles  to  which  the  complement  is  attached. 

Some  modifications  rely  upon  the  patient's  own  complement  and  sheep's  blood 
amboceptor.  Results  obtained  by  such  modifications  must  be  untrustworthy, 
since  the  action  of  amboceptor  upsets  its  complement  action,  and  vice  versa,  for 
both  exist  in  the  same  molecule.  Hence  the  reason  why  so  many  positive  reactions 
are  obtained  in  patients  who  have  never  had  syphilis.  Furthermore,  the  com- 
plementary action  of  different  sera  varies  enormously ;  therefore,  it  is  essential 
that  a  standardised  strength  of  complement  be  employed,  which  means,  in  other 
words,  that  only  the  original  Wassermann  technique  is  reliable. 

Finally,  since  normal  sera  will,  under  certain  conditions,  give  a  positive  reaction, 
any  attempt  to  sharpen  the  reaction  will  increase  the  number  of  positive  results 


RATIONALE    OF   THE   'WASSERMANN   AND   ABDERHALDEN   TESTS.  99 

to  be  obtained  with  normal  sera  ;    therefore  cholesterolised  antigens  had  better 
not  be  emploA'ed. 

For  valuable  assistance  in  this  work  I  wish  to  express  my  thanks  to  Dr.  R.  L. 
Mackenzie  Wallis,  Mr.  J.  Patterson  and  Mr.  W.  H.  Collier. 


'  Bordet  et  Gengou  (1901),  "  Ann.  de  I'lnstitut  Pasteur,"  xv,  289. 

-  Wassermann  u.  Bruck  (1905),  "  Mediz.  Kliiiik.,"    1409. 

'■'  Wassermann  u.  Bruck  (1906),  "  Deutsch.  med.  Woch.,"  sxxii,  450. 

'  Fornet  u.  Schereschewsky  (1907),  "  Miinch.  med.  Woch.,"  liv,  1471. 

5  Miohaelis  (1907),  "  Berl.  kUn.  Woch.,"  xliv,  1477. 

"  Forges  u.  Meier  (1908),  "  Wien.  klin.  Woch.,"  xxxi,  206. 

'  Klausner  (1908),  "  Wien.  klin.  Woch.,"  xxi.  214. 

8  Sohtirmann  (1909),  "Deutsch.  med.  Woch.,"  xxxv,  616. 

»  Jacobsthal  (1909),  "  Jliineh.  med.  Woch.,"  Ivi,  2607. 

"  Levaditi  et  Yamanouchi  (1907),  "  Comptes  Rendus  de  la  Soc.  de  Biol.,"  hx,  740. 

"  Hecht  (1908),  "  Wien.  khn.  Woch.,"  xxi,  1742. 

'^  Fleming  (1909),  "  Lancet,"  i,  1512. 

"  Landsteiner,  Muller  u.  Potz]  (1907),  "  Wien.  klin.  Woch.,"  xx,  1421. 

"  Sachs  (1911),  "  Berl.  khn.  Woch.,"  xlviii,  2066. 

'^  Wechselmann  (1909),  "  Ztsohr.  f.  Immunitatsforsch.,"  iii  (orig.),  525. 

1'^  Ascoli  (1910),  "Miinch.  med.  Woch.,"  Ivii,  63. 

"  Izar  (1910),  "  Miinch.  med.  Woch.,"  Ivii,  182. 

"  Lange  (1910),  "  Deutsch.  med.  Woch.,"  xxxvi,  217. 

"9  Thiele  and  Embleton  (1914),  "  Lancet,"  i,  526. 

20  Browning  (1914),  "  Lancet,"  i,  740. 

"  Mackintosh  and  Fildes  (1912),  "  Zeitschr.  f.  Chemotherapie,"  i,  79. 

"  Rona,  "  Handbuch  der  Bioch.  Arbeitsmethoden,"  v,  328. 

"  McDonagh  and  Mackenzie  Walhs  (1913),  "  Biochemical  Journal,"  \'ii,  517. 

"  Wassermami  u.  Lange  (1914),  "Berl.  klin.  Woch.,"  li,  527. 

=^  Mantovani  (1914),  "  Giorn.  Ital.  d.  Malat.  Vener.  e.  d.  Pelle,"  Iv,  759. 

"  Kaplan  (1913),  "  Xew  York  Med.  Journ.,  "  xcvii,  1172,  and  xcvii,  1267. 

-'  Van  Slyke,  "  Handbuch  der  Bioch.  Arbeitsmethoden,"  v,  995. 

-'  Landsteiner  u.  Rook  (1912),  "Zeitschr.  f.  Immunitatsforschung,"  xvi  (orig.),  14. 

-'  McDonagh  (1914),  "  West  London  Med.  Journ.,"  xix,  1. 

'"  McDonagh  (1914),  "A  Report  upon  the  Biology  of  Sj-philis  "  (Harrison  &  Sons,  London). 

"  Bisgaard  (1914),  "Bioch.  Zeitschr.,"  Iviii,  1. 

2=  McDonagh  (1914),  "  Archiv.  f.  Derm.  v.  Syph.,"  cxix,  205. 

'' Andrewes  (1914),  "Local  Gov.  Board.  Report  of  the  Medical  Officer,"  xliii. 

^*  McDonagh  (1914),  "  Arcliiv.  f.  Derm.  v.  Syph.,"  cxx,  289. 

^'  McDonagh  (1912),  "  Brit.  Med.  Joum.,"  i,  1287. 

««  McDonagh  (1914),  "  Brit.  Journ.  of  Dermatology,"  xxvi,  283. 

"  Abderhalden  (1914),  "  Abwehrfermente,"  4'"  Aufiage.     (J.  Springer,  Berlin.) 

'»  Nerking  (1909),  "  Miinch.  med.  Woch.,"  Ivi,  1475. 

''  Myers  (1914),  "  Lancet,"  i,  767. 


CHAPTER  XI. 

THE   SIGNIFICANCE   OF  THE   WASSERMANN  REACTION,  AND  THE 
AVAY  IN  WHICH  IT  IS  INFLUENCED  BY  TREATMENT. 

A  negative  Widal  does  not  invariably  mean  that  a  patient  is  not  sufiering 
from  enteric  fever,  and  similarly  for  a  negative  Wassermann.  As  a  positive  Widal 
proves  that  the  patient  has  had,  or  has  tj^phoid,  so  does  a  positive  Wassermann 
prove  that  he  has  had,  or  has  syphilis,  although  it  must  be  remembered  that  positive 
reactions  may  be  obtained  in  leprosy,  trj^panosoniiasis,  and  in  some  cases  of  malaria. 

Sporadic  cases  have  been  described,  where  a  positive  Wassermann  has  been 
obtained  in  diseases  other  than  syphilis ;  in  over  16,000  tests  I  have  had  17 
undoubted  instances.  It  is  very  difficult  to  exclude  syphilis,  say  of  some  10,  15 
or  20  years'  standing,  history  being  untrustworthy.     For  instance  : — 

Case  3. — A  man  was  admitted  into  hospital  for  pains  in  the  stomach  region,  and 
vomiting.  Diagnosis,  mahgnant  disease.  Wassermann  positive ;  no  history  or 
sign  of  syphilis.  Operation  was  advised  but  patient  refused.  About  a  year  later 
patient  came  up  to  hospital  complaining  of  pains  in  his  legs.  Again  the  reaction 
was  positive.  He  was  found  to  have  Argyll-Robertson  pupils,  and  the  case  proved 
to  be  one  of  degenerative  myelitis. 

Although  a  positive  reaction  is  a  proof  of  syphihs,  it  must  not  be  forgotten 
that  the  trouble  for  which  the  patient  seeks  advice  is  not  necessarily  svpliihtic. 
Syphilitic  patients  are  by  no  means  immune  to  tuberculosis,  mahgnant  disease,  and 
the  various  forms  of  lymphocytomata,  all  of  which  may  produce  symptoms  which  are 
clinically  very  difficult  to  distinguish  from  those  of  syphilis.  Moreover,  a  positive 
reaction  does  not  necessarily  mean  that  the  patient  has  active  sjrphilis.  Therefore, 
the  only  certain  thing  that  one  can  say  about  a  positive  Wassermann  reaction  is, 
that  the  usual  factors  excluded,  it  signifies  that  the  patient  has  had  syphilis. 

The  many  modifications  of  the  reaction  which  have  been  made,  have  increased 
the  incidence  of  positive  reactions  in  persons  who  have  never  had  syphilis.  The 
reaction  which  Wassermann  described  is  laborious,  but  nevertheless  is  the  most 
trustworthy.     Since  the  reaction   is   empirical,  all    efforts   should    be  made  to  do 


INTERPRETATION   OF   REACTION   AND    INFLUENCE    OF   TREATMENT    UPON    IT.       101 

away  with  the  empiricism,  before  attempting  to  simplify  the    technique.      The 
reader  will  find  in  chapter  X  an  attempt  to  achieve  the  former. 

The  interpretation  of  a  positive  and  negative  Wassermann  reaction  will  be 
as  follows,  according  to  the  various  stages  of  the  disease  : — 

Stage  of  the  Initial  Lesion. 

In  this  stage  the  reaction  is  alwa3^s  negative.  Should  a  positive  reaction 
be  obtained  in  a  case  of  a  doubtful  sore,  it  is  tolerably  certain  that  the  sore  is 
syphilitic,  and  it  means  that  the  patient  has  entered  the  generalisation  stage. 

Stage  of  the  Generalisation  of  the  Virus. 

The  Wassermann  reaction  becomes  positive,  as  a  rule,  before  any  signs  or 
symptoms  of  this  stage  manifest  themselves.  The  Wassermann  reaction  may 
become  positive  as  early  as  the  fifteenth  day  after  the  first  appearance  of  the 
sore,  but,  as  a  rule,  it  does  not  become  positive  until  about  the  thirty-fifth  day. 
In  6'5  per  cent,  of  cases,  in  spite  of  obvious  sj'mptoms,  the  Wassermann  reaction 
is  negative. 

Recurrent  Stage. 

If  the  reciu:rence  occurs  before  the  fourth  year,  or  thereabouts,  and  if  the 
patient  has  received  no  treatment  within  the  last  six  months,  the  reaction  will  be 
positive  in  practically  every  case.  The  longer  the  interval  that  intervenes,  from 
the  fourth  year  until  the  appearance  of  the  recurrence,  the  greater  the  chance 
of  the  Wassermann  reaction  being  negative,  so  that,  in  the  stage  of  the  late 
recurrences,  the  Wassermann  reaction  may  not  be  positive  in  more  than  75  per 
cent,  of  the  cases.  This  is  due,  as  may  have  been  seen  in  the  last  chapter,  to  a 
free  fatty  acid  particle  existing  in  the  lipoid-globulin  or  reagin  molecule.  The 
effect  of  treatment  upon  this  molecule  often  makes  itself  felt  for  a  few  months, 
hence  a  careful  interpretation  of  a  negative  AVassermann  reaction  should  be  made, 
if  any  treatment  has  been  administered  during  the  last  six  months. 

Latent  Stage. 

This  is  one  of  the  most  important  stages  of  the  disease,  and  is  one  in  which 
the  Wassermann  reaction  is  of  the  least  value.  The  latent  stage  is  the  stage  in 
which  the  patient  has  had  syphilis,  has  been  treated,  and  shows  absolutely  no 
symptoms  of  the  disease  after  a  very  careful  clinical  examination.  To  give  accurate 
figures  per  cent.,  in  which  the  Wassermann  reaction  is  positive  in  this  stage,  is 
impossible,  since  so  many  factors  come  into  play,  such  as  the  kind  of  infection, 


102  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

the  time  that  has  elapsed  since  the  infection,  the  amount  of  treatment  the 
patient  has  had,  the  stage  in  which  the  patient  was  when  the  treatment  was 
commenced,  the  date  when  the  patient  last  had  treatment,  and  whether  he  has 
had  a  recurrence  or  not. 

Let  us  take  each  of  these  factors  in  turn,  and  assume  that  in  every  case  the 
syphilis  was  contracted  not  less  than  four  years  prior  to  the  date  when  the  patient 
seeks  advice,  as  this  is  about  the  period  at  which  the  latent  stage  can  be  said  to 
have  begun. 

(a)  The  hind  of  infection. — If  the  infection  was  mild,  the  check  upon  the 
production  of  antibodies  will  have  probably  commenced  about  the  fourth  3'ear, 
and  therefore  the  Wassermann  reaction  will  be  negative.  This  does  not  necessarily 
mean  that  the  patient  is  cured,  as  he  may  develop  a  degenerative  nerve  lesion 
or  even  a  systemic  lesion,  later.  If  the  infection  was  severe,  the  production  of 
reagin  often  continues  throughout  the  patient's  life  time,  hence,  about  the  fourth 
year,  the  Wassermann  reaction  will  be  positive.  This  does  not  necessarily  mean 
that  the  patient  has  active  syphilis. 

\h)  The  amount  of  treatment. — The  more  treatment  the  patient  has  had,  the 
greater  the  likelihood  that  the  Wassermann  reaction,  about  the  fourth  year,  will 
be  negative,  and  vice  versa,  but  the  results  can  convey  no  meaning,  as  a  negative 
reaction  is  not  definite  proof  that  the  patient  is  cured,  and  a  positive  reaction  may 
only  be  an  indication  of  the  patient's  protective  capacity  against  the  disease. 

(c)  The  stage  of  the  disease  at  which  treatment  teas  commenced. — If  the  Wasser- 
mann reaction  was  negative  before  treatment  was  started,  and  negative  again  about 
the  fourth  year,  the  patient  can  almost  certainly  be  assured  that  he  is  cured.  If 
the  Wassermann  reaction  was  positive  before  treatment  was  begun,  neither  a 
positive  nor  a  negative  Wassermann  reaction,  about  the  fourth  year,  means 
anything. 

(d)  The  date  when  the  paiient  last  had  treatment. — The  more  recent  the  treatment, 
the  greater  the  likelihood  of  the  reaction  being  negative,  and  the  less  the  reliUnce 
that  can  be  placed  upon  the  test. 

(e)  Whether  the  patient  has  had  a  recurrence  or  not. — If  the  patient  has  had 
a  recurrence,  the  chances  are  that  the  reaction  will  be  positive,  in  spite  of  treatment. 
If  negative,  on  the  other  hand,  the  chances  are  that  the  patient  is  cured,  but  there 
are  several  traps  that  await  the  physician  who  feels  sure  himself  that  the  patient 
is  cured.  The  chemical  configuration  of  the  reagin  molecule  may  be  such  that 
it  will  prevent  adsorption  of  complement  in  vitro,  and  this  is  a  condition  which 
is  very  apt  to  occur  in  the  sera  of  those  patients  who  have  had  a  recurrence. 

I  now  practically  never  do  a  Wassermann  reaction  in  this  stage,  for  the  simple 


INTERPRETATION    OF    REACTION   AND    INFLUENCE    OF   TREATMENT   UPON   IT.      103 

reason  that  a  positive  reaction  may  only  mean  that  the  patient's  protective 
mechanism  is  working  well,  and  requires  no  stimulus  ;  treatment  is  by  no  means 
indicated — indeed,  it  may  even  be  a  contraindication,  as  I  have  seen  several  cases 
in  which  I  am  certain  that  a  degenerative  nervous  lesion  was  precipitated,  owing 
to  the  check  which  treatment  put  upon  the  production  of  systemic  antibodies 
{vide  Chapters  XXIII  and  XXIV). 

I  examine  the  patient  thoroughly,  and  if  I  can  find  nothing  wrong,  I  assure 
him  that  all  is  well,  and  send  him  out  a  happier  man  than  he  came  in.  If  I  am 
the  least  bit  suspicious,  and  I  pay  particular  attention  to  any  nervous  signs  or 
symptoms,  I  examine  the  cerebro-spinal  fluid,  and  base  my  advice  to  the  patient 
upon  the  conditions  found  therein  {vide  Chapter  XXII). 

Syphilis  in  Women. 

The  infection  of  women  can  be  divided  into  two  classes,  («)  ordinary  infection, 
(b)  conceptional  infection.  Only  the  latter  need  be  discussed,  as  the  former  does 
not  differ  from  the  infection  of  the  male,  but  it  must  always  be  remembered  that, 
broadly  speaking,  the  sera  of  women,  during  the  child  bearing  period,  have  a 
tendency  to  give  negative  Wassermann  reactions.  In  what  may  be  called  con- 
ceptional syphihs,  that  is  when  the  mother  and  embryo  are  infected  by  the 
contaminated  semen,  the  Wassermann  reaction  is  often  negative.  I  have  fre- 
quently had  cases  in  which  the  mother  has  given  birth  to  an  undoubted  syphilitic 
infant,  and  yet  her  blood  has  given  a  negative  reaction.  Pregnancy  no  doubt 
retards  or  prevents  the  development  of  the  Leucocytozoon  syphilidis  for  the 
time  being. 

Some  time  after  a  pregnancy,  should  another  not  supervene,  or  after  the  child 
bearing  period  is  over,  the  reaction  frequently  becomes  positive.  In  some  cases 
repeated  pregnancies  have  undoubtedly  resulted  in  a  spontaneous  cure  of  the 
disease. 

Congenital  Syphilis. 

It  may  be  mentioned  first,  that  when  one  wishes  to  get  blood  from  a  new 
born  infant,  it  is  best  to  puncture  the  heel.  Infants  born  with  S3Tnptoms  of  the 
disease  always  give  a  positive  reaction.  Syphilitic  infants,  born  without  symptoms 
of  the  disease,  may  not  give  a  positive  reaction  until  symptoms  appear.  The 
reaction  is  always  positive  in  Syphilis  congenita  tarda,  and  it  may  remain  so 
throughout  life,  although,  in  the  majority  of  cases,  the  tendency  is  for  it  to 
become  negative  in  time. 

Case  4. — A  girl  aged  23,  unmarried,  had  signs  of  an  old  bilateral  interstitial 
keratitis,  she  was  stone  deaf  in  both  ears,  she  had  Hutchinson's  teeth,  and  marked 


10-i  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

signs  of  old  osteoperiostitis,  but,  in  spite  of  all  this,  her  blood  was  negative  on  every 
occasion  it  was  tested. 

I  have  had  almost  similar  cases,  in  which  the  blood  of  congenital  syphilitics 
between  40  and  50  3^ears  of  age  has  been  positive,  and  I  have  had  two  cases  in 
which  a  congenital  syj^hilitic  mother  has  given  birth  to  children,  whose  blood 
has  given  a  positive  Wassermann  reaction.  Usually  the  blood  of  infants  born 
of  congenital  syphilitic  parents  gives  a  negative  reaction. 

Treatment  has  very  little  influence  upon  the  reaction  in  congenital  syphilis. 

Syphilis  of  the  Nervous  System. 

In  early  arterial  lesions,  the  blood  is  almost  invariably  positive,  while  in 
late  arterial  cases,  it  is  frequently  negative.  In  meningeal  syphilis,  the  blood  may 
be  either  negative  or  positive.  As  in  many  of  the  cases  of  .syphilitic  meningitis, 
symptoms  do  not  arise  until  the  host  has  ceased  to  form  protective  bodies  in  his 
systemic  portion,  it  will  naturally  follow  that  the  blood  will  often  be  negative. 

In  degenerative  nerve  lesions,  when  the  condition  first  commences,  the  blood 
may  be  positive  or  negative.  If  positive,  the  chances  are  that  the  patient  has  a 
systemic  vascular  lesion,  which  not  infrequently  accompanies  degenerative  nerve 
lesions.  In  those  cases  in  which  the  blood  is  negative  at  first,  it  usually  becomes 
positive  later,  especially  is  this  the  case  in  degenerative  encephalitis,  when  sufficient 
reagin,  which  is  formed  in  the  nerve  tissue,  percolates  into  the  general  blood  stream. 
As  more  reagin  gets  formed  in  degenerative  encephaUtis,  than  in  degenerative 
myelitis,  it  naturally  follows  that,  in  the  former  the  blood  more  often  gives  a 
positive  Wassermann  reaction. 

If  later  still,  the  blood  becomes  negative,  and  the  case  is  one  of  degenerative 
encephalitis,  it  generally  means  that  the  patient  is  in  a  quiescent  period.  If  the 
case  is  one  of  degenerative  myelitis,  the  chances  are  that  spontaneous  cure  has 
resulted — a  by  no  means  uncommon  sequence  to  the  condition.  , 

Differential  Diagnosis. 

The  Wassermann  reaction  is  sometimes  useful,  when  one  is  dealing  with  a 
differential  diagnosis,  but  it  is  perfectly  true  to  say  that,  the  more  it  is  used  for 
this  purpose,  the  less  the  clinical  knowledge  of  the  physician  who  uses  it.  Clinical 
knowledge  is  the  highest  attainment  in  medicine,  hence,  the  present,  and  all  future 
generations  would  be  better  advised  to  place  less  reliance  upon  this,  and  all  other 
tests,  and  to  regard  them  as  mere  adjuncts  to  a  clinical  diagnosis. 

I  have  been  carrying  out  Wassermann  tests  since  early  in  the  year  1908.  I 
have  had  the  clinical  history  of  most  of  the  cases  examined,  and  I  have  in  all  done 


INTERPRETATION   OF   REACTION   AND    INFLUENCE    OF   TREATMENT    UPON   IT.       105 

over  16,000  tests.  Early  in  the  year  1915,  I  am  able  to  say  that  scarcely  ever 
an  opportunity  arises  in  which  the  performance  of  the  reaction  is  called  for,  and 
even  in  those  cases  in  which  the  result  is  positive,  in  the  majority  of  instances, 
it  is  impossible  to  say,  whether  it  means  that  the  patient  has  active  syphilis,  or 
only  that  he  has  had  the  disease. 


The  Wassermann  Reaction  as  Influenced  by  Treatment. 

In  the  primary  stage,  when  the  reaction  is  negative  before  treatment  with 
salvarsan  is  commenced,  most  cases  give  a  positive  reaction  after  treatment.  This 
is  most  marked  about  the  forty-eighth  hour,  but  commences  to  show  itself  about 
the  seventeenth  hour.  In  some  cases,  on  the  other  hand,  the  reaction  does  not 
become  positive  until  the  fifth  day. 

Although  it  may  remain  positive  for  several  days,  the  degree  diminishes 
generally  about  the  third  week,  till  it  becomes  negative  before  the  eighth.  If  the 
reaction  is  only  slightly  positive  after  the  injection,  it  becomes  negative  much  earlier. 
If  the  serum  is  tested  in  diminishing  strengths,  to  estimate  its  reagin*  content,  one 
can  form  an  approximately  accurate  opinion  as  to  how  close  to  the  generalisation 
stage  the  patient  is,  and,  roughly,  how  many  subsequent  injections  will  be 
necessary  to  produce  a  possible  cure. 

If  the  first  injection  gives  rise  to  only  a  weak  reaction,  then  three  or  four  more 
will  undoubtedly  suffice  to  make  the  reaction  negative  ;  if,  however,  the  reaction 
is  strong,  then  the  patient  is  in  the  generalisation  stage,  and  will  require  at  least 
3  grams  of  salvarsan  or  neo-salvarsan,  before  the  desired  effect  is  obtained. 

Case  5. — Intra-urethral  chancre,  14  days'  duration,  six  weeks  after  inter- 
course ;  slight  inguinal  adenitis  ;  spirochaetae  found. 


No.  of  Injection,  and  Result. 


24  Hours 

48  Hours 

5th 

10th 

after. 

after. 

Day. 

Day. 

+  + 

+  +  + 

+  +  + 

+ 

+  + 

— 

+  +  + 

+  +  + 

— 

— 

+ 

— 

+ 

14th 
Day. 


1st  injection     ...  ...[     — 

2nd  injection  (8th  day  after  1st)  ...'-|-  +  -|- 

3rd  injection  (21.st  day  after  2nd)  . . . j  +  + + 

4th  injection  (8th  day  after  3rd)  ...'  +  +  + 

5th  injection  (14th  day  after  4th)  ...      — 

6th  injection  (8th  day  after  5th)  ...      + 


+  +  + 


The  reaction  was  tested  on  the  seventh,  fourteenth,  twenty-first  and  twenty- 
eighth  days  after  the  last  injection,  and  was  negative  on  each  occasion.     Patient 

*  Since  the  reacting  substance  in  the  Wassermann  reaction  is  not  a  true  antibody,  it  has 
received  the  name  of  "  reagin." 


]06 


THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT    OF   SYPHILIS. 


was  put  on  mercury  for  a  year,  and  six  months  afterwards  Wassermann  reaction 
was  positive.  Patient  has  never  developed  a  recurrence.  The  blood  has  been 
tested  several  times  since  it  was  last  positive,  and  sometimes  it  gives  a  negative 
reaction  and  sometimes  a  positive  one.  Paradoxical  sera  are  not  uncommonly 
met  with  in  patients,  who  have  been  well  treated. 

Case    6. — Two  chancres  on  penis,  two  on  scrotum  ;    no  adenitis  ;    date    of 
infection  not  clear  ;  spirochaetae  found. 


Xo.  of  Injection,  and  Result. 


24  Hours 
after. 


48  Hours 
after. 


5th  Day. 


1st  injection 

2ncl  injection  {8th  day  after  1st) 
3rd  injection  (8th  day  after  2iid) 
4th  injection  (8th  day  after  3rd) 


+  + 
+  + 


+ 

+ 


+  + 
+  + 


The  reaction  was  tested  on  the  seventh,  fourteenth,  twenty-first  and  twenty- 
eighth  days  after  the  last  injection,  and  was  negative  on  each  occasion. 

The  reaction  was  tested  again,  one  and  two  years  later,  with  negative  results. 

Case  7. — Chancre,  internal  canthus  of  eye  ;  adenitis,  pre-auricular  and 
cervical ;  date  of  infection  uncertain  ;  spirochaetae  found. 


No.  of  Injection,  and  Result. 

24  Hours 
after. 

48  Hours 
after. 

5th 
Day. 

10th 
Day. 

17th 
Day. 

1st  injection 

2nd  injection  (8th  day  after  1st) 
3rd  injection  (17th  day  after  2nd)   ... 
4th  injection  (8th  day  after  3rd) 
5th  injection  (21st  day  after  4th)    ... 

-I--I--H 
+  + 

-|--t- 

+  + 

+ 

+  +  + 

+  -I- 

4--t- 

+ 

+  + 

On  testing  the  reaction  on  the  seventh,  fourteenth,  twenty-first  and  twenty- 
eighth  days  after  the  last  injection,  it  was  found  to  be  negative  ou  each  occasion. 
Mercury  was  given  for  one  year,  and  blood  was  tested  again  six  months  and  a  year 
later  ;  on  the  latter  occasion  it  gave  a  positive  result.  This  patient  has  had  no 
recurrence,  and  the  blood  tested  since  has  sometimes  been  positive  and  sometimes 
negative. 

Unfortunately,  it  is  rare  to  get  a  case  so  early  that  the  reaction  does  not 
become  positive  as  the  result  of  an  injection.  I  have  had  some  cases  however, 
but  nevertheless  I  give  three  or  four  more  injections  of  neo-salvarsan,  for  safety. 
In  every  case,  mercury  should  be  prescribed,  for  from  12  to  18  months. 


INTERPRETATION   OF   REACTION   AND   INFLUENCE    OF    TREATMENT   UPON   IT.        107 


WTien  the  reaction  becomes  strongly  positive  after  an  injection,  and  in  cases 
in  which  it  is  markedly  positive  before  treatment  is  commenced,  it  may  be  assumed 
at  once  that  the  patient  is  in  the  generalisation  stage,  and  that  he  should  receive 
the  treatment  mapped  out  for  this  stage  {vide  Chapter  XXIX). 

Case  8. — Chancre  on  penis,  general  adenitis,  and  headaches  at  night  time. 


No.  of  Injection,  and  Result. 

24  Hours 
after. 

48  Hours 
after. 

5th  Day. 

1st  injection      

2nd  injection  {8th  day  after  1st)       

3rd  injection  (8th  day  after  2nd)      

4th  injection  (8th  day  after  3rd)       

+  +  + 

+  +  + 

+ 

+  +  + 
+ 

+  +  + 

+ 
+ 

+  +  + 
+  + 
-  + 

The  reaction  was  also  found  to  be  negative  on  the  seventh,  fourteenth,  twenty- 
first  and  twenty-eighth  days  after  the  last  injection.  Mercury  was  prescribed  for 
18  months,  but  six  months  later  Wassermann  reaction  was  positive.  Patient  has 
since  developed  a  meningo-myelitis,  in  spite  of  the  fact  that  the  "Wassermann 
reaction  in  the  blood  has  been  negative  for  some  time  past. 

Case  9. — A  typical  case  of  early  generalised  syphilis,  rash,  sore  throat,  etc. 


No.  of  Injection,  and  Result. 


24  Hours 

after. 


48  Hours 
after. 


5th  Day. 


1st  injection 

2nd  injection  (8th  day  after  1st) 
3rd  injection  (8th  day  after  2nd) 
4th  injection  (8th  day  after  3rd) 
5th  injection  (8th  day  after  4th) 
6th  injection  (8th  day  after  5th) 
7th  injection  (8th  day  after  6th) 


+  +  + 
+  +  + 

+  + 
+  +  + 


+  +  + 
+  +  + 
+  +  + 
+  +  + 


+  +  + 

+  +  + 
+  + 

+  +  + 
+  + 


+  +  + 
+  +  + 
+  +  + 

+ 


The  reaction  was  also  found  to  be  negative  on  the  tenth,  fourteenth,  and 
twenty-eighth  days  after  the  last  injection.  Mercury  was  taken  for  six  months 
only ;  six  months  later  Wassermann  reaction  was  negative,  but  a  year  later  it 
had  become  positive  again. 

In  the  late  stages,  the  Wassermann  reaction  behaves  much  in  the  same  way  as 
it  does  in  the  primary  and  generalisation  stages,  except  for  one  peculiar  phenomenon, 
which  is  occasionally  to  be  noted,  that  is,  that  a  case  with  a  strong  positive  reaction, 
before  treatment,  may  become  negative  immediately  after  an  injection,  and  remain 
so  from  2-1  to  72  hours,  and  then  become  quite  positive  again.  On  repeating  the 
injection,  the  same  thing  may  happen,  but  more  often  it  is  quite  the  reverse,  namely. 


108 


THE   BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   SYPHILIS. 


that  the  reaction  becomes  more  positive,  au  occurreuce  which  is  seen  in  the 
early  stages.  The  opposite  also  frequently  occurs,  i.e.,  a  patient  with  late  lesions, 
giving  a  negative  reaction,  gives  a  positive  reaction  after  an  injection  of  salvarsan. 
Case  10. — The  patient  contracted  syphihs  25  years  ago,  for  which  he  took 
mercury  at  irregular  intervals  for  four  years.  For  the  past  five  years  he  had  been 
troubled  with  cutaneous  gummata,  which  disappeared  under  mercury  and  iodides, 
to  reappear  quickly  after  treatment  was  discontinued.  In  1911  the  patient  had 
three  intramuscular  injections  of  salvarsan,  and  he  came  up  for  a  Wassermann 
test  just  after  Christmas  of  the  same  year.     There  were  no  s)Tiiptoms  at  the  time. 


No.  of  Injection,  and  Result. 

24  Hours 
after. 

48  Hours 
after. 

5th  Day. 

1st  injection      

2nd  injection  (8th  day  after  1st)        

3rd  injection  (8th  day  after  2nd)       

■4th  injection  (8th  day  after  3rd)        

5th  injection  (8th  day  after  ith)        

6th  injection  ( 8th  day  after  5th)       

+  +  + 

+  +  + 

+  +  + 

+  + 

+  +  + 

+  +  + 

+  + 

+ 

+  +  + 

+  +  + 

+  +  + 

+ 

+  +  + 

+  +  + 

+  +  + 

+ 

Six  months  and  a  year  later,  although  patient  was  under  mercury,  the  Wasser- 
mann reaction  was  positive,  but  since  then  it  has  remained  negative. 

Case  1 1 . — A  man,  aged  42,  18  years  ago  contracted  syphihs,  for  which  he  was 
treated  with  mercury  (pills)  internally  for  three  years.  A  few  years  later  he  was 
much  troubled  with  headaches,  which  were  only  relieved  by  mercury  and  iodides  ; 
and  the  moment  treatment  was  stopped,  the  headaches  commenced  again.  From 
time  to  time,  the  patient  had  cutaneous  gummata  and  some  soft  nodes  (gimimatous 
pericranitis)  on  his  skull.  When  he  came  up  for  advice  he  had  a  gumma  over  his 
frontal  bone,  and  it  had  eroded  a  portion  of  the  external  table  ;  headaches  were 
bad,  and  the  patient  complained  bitterly  of  losing  his  memory. 


No.  of  Injections,  and  Result. 


24  Hours 
after. 


48  Hours 
after. 


5th  Day. 


lat  injection 
2nd  injection 
3rd  injection 
4th  injection 
5th  injection 
6th  injection 
7th  injection 
8tli  injection 
9th  injection 


(8th  day  after  1st) 
(28th  day  after  2nd) 
(8th  day  after  3rd) 
(8th  day  after  4th) 
(8th  day  after  5th) 
(8th  day  after  6th) 
(8th  day  after  7th) 
(8th  day  after  8th) 


+  +  + 
+  +  + 
+  +  + 
+  +  + 
+  +  + 

+  + 
+  +  + 

+  + 
+ 


+  + 

+  + 

+ 


+ 


+  +  + 

+  +  + 

+  + 

+ 

+  + 

+ 


+  +  + 

+  +  + 
+  +  + 
+  +  + 

+ 


INTERPEETATION   OF   REACTION   AND   INFLUENCE    OF   TREATMENT   UPON   IT.       101) 

On  testing  the  reaction  on  the  seventh,  fourteenth,  twenty-first,  and  twenty- 
eighth  days  after  the  last  injection,  it  was  found  to  be  negative  on  each  occasion, 
and  has  remained  negative  for  three  years. 

When  approaching  the  end  of  treatment,  and  when  all  the  reactions  are  negative, 
and  in  cases  in  which  the  amount  of  reagiu  is  normally  small,  namely,  in  cases  of 
arteriosclerosis,  cerebro-spinal  syphiUs,  sj'phihtic  epilepsy,  and  hemiplegia,  each 
serimi  should  be  tested  in  gradient  increasing  strengths. 

When  a  serum  stronger  than  normal  is  used,  controls  should  never  be  omitted, 
to  show  that  it  has  no  haemolytic  power  on  the  sheep's  blood  corpuscles,  an  occur- 
rence which  is  not  at  all  uncommon,  especially  when  the  serum  has  been  allowed  to 
remain  with  its  corpuscles  for  a  few  days.  Therefore  it  is  desirable  to  pipette  ofi 
the  serum  as  soon  as  possible  after  the  blood  has  been  withdrawn,  and  it  is  always 
better  to  inactivate  the  serum  as  soon  as  possible,  since  sera  left  at  room  temperature, 
or,  more  especially,  in  an  ice  incubator,  soon  acquire  the  property  of  fixing 
complement. 

It  sometimes  happens  that  cases  nearing  the  end  of  treatment,  for  instance, 
after  the  fourth  or  fifth  injection,  give  a  weak  positive  reaction  only  between  the 
third  and  fom'th  week,  and  it  becomes  negative  within  a  few  hours  of  repeating 
the  injection. 

Patients  who  have  had  syphilis,  and  give  a  negative  Wassermanu  reaction, 
are  either  cured  or  in  the  latent  stage  ;  which  of  the  two  can  sometimes  be 
ascertained  by  giving  a  provocative  injection  of  salvarsan,  and  then  testing  the 
blood. 

Case  12. — A  man,  aged  29,  contracted  syphihs  five  years  ago.  The  attack 
was  very  mild,  but  nevertheless  the  patient  continued  his  mercury  treatment  (pills 
and  injections)  for  four  years.  A  recurrence  never  appeared.  On  three  different 
occasions  the  blood  had  given  a  negative  Wassermann  reaction,  but  the  patient 
being  anxious  to  marry  was  desirous  of  an  injection  of  "  606  "  to  make  things  sure. 


Xo.  of  Injection,  and  Result. 


1st  injection... 

2ud  injection  (8th  day  after  1st)  ... 
3rd  injection  (8th  day  after  2nd)  ... 
4th  injection  (8th  day  after  3rd)  ... 
5th  injection  (21st  day  after  4th)... 
6th  injection  (8th  day  after  5th)  ... 
7th  injection  (8th  day  after  6th)  ... 


24  Hours 

after. 


48  Hours 

after. 


5th  Day. 


14th  Day. 


' 

+ 

-f-n- 

_ 

— 

+ 

-1-  +  + 

-f-l- 

— 

+ 

-1- 

+  + 

.     -1- 

+ 

+ 

+ 

.     + 
.    +- 

— 

— 

— 

- 

— 

110  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

The  reaction  was  also  negative  on  tlie  seventh,  fourteenth,  twenty-first, 
and  twenty-eighth  days  after  the  last  injection.  Mercury  was  prescribed  for 
a  year,  and  up  to  the  second  year  the  reaction  was  negative  every  time  it  was 
tested. 

If  the  previous  treatment  has  been  recent — that  is,  only  a  few  months  ago — 
the  appearance  of  a  positive  reaction  may  be  delayed,  or,  as  happened  in  several 
cases,  may  be  positive  in  the  IS  hours  blood,  and  negative  again  on  the  fifth  or 
even  the  third  day,  to  become  only  definitely  positive  on  each  occasion  after  the 
second  injection.  In  a  few  cases,  the  reaction  was  not  positive  at  all,  until  after 
the  second  injection — cases  of  arterial  syphilis. 

Not  only  is  the  reaction  determined  by  the  time  of  the  previous  treatment, 
but  also  largely  by  the  quality  of  that  treatment.  If  the  treatment  has  been  good, 
then  the  occurence  of  a  positive  reaction  may  also  be  delayed,  and  only  a  few 
injections  are  required  to  produce  a  negative  reaction. 

Several  of  my  patients,  who  had  been  treated  with  mercury  for  from  three  to 
four  years,  and  who  had  given  a  negative  Wassermann  reaction  on  several 
occasions,  gave  a  positive  one  after  a  provocative  injection  of  salvarsan,  and 
required  from  four  to  six  injections  before  a  negative  reaction  was  obtained. 
Whether  a  positive  reaction  after  a  provocative  injection  of  salvarsan  means  that 
the  patient  has  an  active  lesion,  a  hidden  focus,  or  only  signifies  that  he  has  had 
syphilis,  I  am  not  at  present  able  to  state  definitely.  My  own  opinion  is,  that  it 
only  means  that  the  patient  has  had  syphilis,  therefore  it  is  very  seldom  that  I 
now  give  a  provocative  injection.  I  rely  upon  a  clinical  examination,  or  upon  an 
examination  of  the  cerebro-spinal  fluid,  to  guide  me  as  to  whether  further  treatment 
is  required  or  not.  If  no  treatment  is  required,  most  patients  assume  that  they 
are  cured,  and  do  not  ask  the  question.  If  they  do,  I  explain  the  whole  situation 
to  them,  with  the  result  that  the  visit  ends  happily.  Giving  a  provocative  injection 
and  doing  a  series  of  tests  in  which  absolute  faith  cannot  be  put,  only  tend  to  make 
the  patient  suspicious  and  more  concerned  about  himself,  a  state  of  mind  which  no 
venereal  patient  should  be  allowed  to  develop. 

In  cases  of  cerebro-spinal  meningitis,  in  which  the  cerebro-spinal  fluid  gives 
a  positive  Wassermann  reaction,  repeated  injections  of  salvarsan  may  convert 
the  positive  into  a  negative  reaction,  and  at  the  same  time  cause  the  lymphocytosis 
to  disappear,  but,  in  the  majority  of  cases,  the  reactions  become  positive  again, 
sooner  or  later.  As  the  cerebro-spinal  fluid  is  weak,  both  in  its  reagin  content 
and  in  complement-fixing  capacity,  it  should  invariably  be  tested  in  increasing 
strengths  up  to  1,000  per  cent. 

In   cerebro-spinal    syphihs,    it   is    not   at   all    uncommon   to    find    that   the 


INTERPRETATION   OF   REACTION   AND    INFLUENCE    OF   TREATMENT   UPON    IT.      Ill 

Wassermann  reaction  is  negative  in  the  blood,  and  positive  in  the  cerebro- 
spinal fluid,  becoming  positive  in  the  former  only  after  treatment. 

In  degenerative  nerve  lesions,  treatment,  however  drastic  it  is,  is,  in  the 
majority  of  cases,  quite  unable  to  render  a  positive  Wassermann  reaction  in  the 
cerebro-spinal  fluid  negative  ;  the  globulin  reaction  seldom  disappears,  but  the 
lymphocytosis  may  vanish. 

However  many  injections  of  salvarsan  be  given,  it  is  always  wise  to  supplement 
them  with  at  least  one  year's  treatment  by  mercurial  injections  and  iodides.  Even 
then  one  may  not  be  successful  in  preventing  a  recurrence  from  appearing  later, 
as  no  test  exists  which  will  prove  the  absence  or  presence  of  spores,  and  no  treatment 
exists  which  will  kill  them  directly,  provided  they  have  been  in  the  body  for  a 
sufficiently  long  time. 

If  the  above  course  is  followed,  experience  has  so  far  shown  that  a  cure  in  the 
primary  and  generalisation  stages  of  syphilis  is  possible,  but  by  no  means  certain. 
In  the  late  cases  a  cure  is,  for  the  most  part,  impossible.  Therefore,  in  the  early 
stages  of  sj'philis,  in  my  opinion,  salvarsan  can  be  used  with  the  idea  of  curing  the 
disease,  and  in  some  of  the  late  stages  with  the  idea  of  abolishing  the  STOiptoms 
onl}'.  There  is  no  doubt  that  many  patients  who  have  shown  recurrent  symptoms 
become  spontaneously  cured ;  even  in  a  chronic  condition  like  degenerative 
myelitis,  it  is  highly  probable  that  a  spontaneous  cure  occurs  in  about  20  per  cent, 
or  more  of  all  cases. 

Nearly  every  case  which  1  have  treated  by  several  injections  of  salvarsan  and 
one  or  more  years'  treatment  with  mercury  has,  up  to  the  present,  remained  free 
of  symptoms,  and  some  have  been  under  observation  for  four  years  from  the  time 
treatment  was  begun.  A  majority  of  the  cases  has,  however,  later  given  positive 
Wassermann  reactions,  and  a  peculiarity  about  most  of  them  has  been  that  the 
reaction  appeared  paradoxical,  i.e.,  one  week  or  one  month  it  was  positive,  while 
the  next  week  or  month  it  was  negative  again.  The  cause  of  this  paradox  is  far 
from  clear,  but,  nevertheless,  its  occurrence  should  be  a  stimulus  to  make  us  probe 
the  rationale  of  the  Wassermann  reaction  down  to  the  very  bottom,  to  see  if  we 
are  justified  in  always  regarding  a  positive  reaction  as  necessarily  indicative  of 
active  s}"philis. 

It  is  noteworthy  that  of  two  individuals,  in  exactly  the  same  stage  of  disease, 
with  the  same  lesions,  one  may  give  a  negative  reaction  after  four  injections,  while 
in  the  other,  six  or  more  may  be  required  before  a  negative  reaction  is  obtained. 
Again,  a  permanent  negative  reaction  is  most  easily  obtained  when  the  treatment 
is  continuous,  that  is  when  the  injections  of  salvarsan  follow  closely  upon  one 
another,  and  when  mercury  is  given  afterwards  for  a  year  or  more.   For  instance,  early 

H 


112  THE    BIOLOGY,    CLINICAL  ASPECT   ANB   TREATMENT   OF    SYPfflLIS. 

cases  of  sj^hilis,  which  had  received  one  or  two  iujections  of  salvarsan  several 
months  back,  have  required  nearly  the  same  number,  given  continuously,  as 
presumably  would  have  been  required,  had  those  previous  injections  not  been 
given.  Therefore  it  is  important,  if  a  course  is  going  to  be  started,  that  it  should 
be  persevered  with,  until  the  desired  effect  is  obtained. 

'  As  my  views  have  altered  considerably  since  the  time  when  I  was  prompted 
to  do  the  research  work,  of  which  the  above  is  the  outcome,  I  now  never  gauge 
my  treatment  by  the  Wassermann  reaction.  I  give  the  patient  the  maximum 
amount  of  treatment  which  I  have  learnt  by  experience  is  necessary  for  those 
cases,  in  which  a  cure  by  treatment  is  contemplated ;  while  the  other  patients 
I  treat  symptomatically.  The  reader  will  have  seen  that  the  result  of  treatment 
upon  the  Wassermann  reaction  is  extremely  paradoxical,  and  therefore  I  refer 
him,  when  he  has  the  treatment  of  a  case  under  consideration,  to  Chapter  XXIX. 


CHAPTER  XII. 
THE   CUTIREACTION. 

Since  v.  Pirquet  demonstrated  that  the  diagnosis  of  tuberculosis  might 
be  assisted  by  the  reaction  produced  by  an  intracutaneous  injection  of  tuberculin, 
several  observers  have  tried  to  find  a  similar  test  for  syphilis.  At  that  time  the 
SpirocJiaefa  pallida  could  not  be  grown  in  culture,  consequently  tissue  extracts, 
which  contained  this  organism,  were  used.  Tedeschi^  was  the  first  to  use  the 
cuti-  and  ophthalmoreaction  in  cases  of  syphilis.  He  employed  an  aqueous  extract 
of  chancres,  which  had  been  passed  through  a  Berkefeld  filter.  Tedeschi  obtained 
positive  results  in  animals  which  had  been  inoculated  with  syphilis,  but  he  appears 
to  have  made  no  control  vaccinations  on  man. 

Meirowsky,'  about  a  year  later,  used  an  extract  of  syphilitic  liver,  with  satis- 
factory results,  but  he  found  in  his  experiments  that  tuberculous  patients  also 
gave  a  positive  reaction. 

Ciufio^  repeated  Meirowsky's  work,  but  came  to  the  conclusion  that  the  reaction 
was  not  specific. 

In  1910,  Nicolas,  Favre,  Gautier,  and  Charlet*  made  a  glycerin  extract  of  foetal 
syphihtic  liver,  to  which  they  gave  the  name  of  "  syphihn,"  and,  according  to  their 
reports,  the  results  were  very  satisfactory,  but  subsequent  workers  failed  to  confirm 
them.  When  it  became  known  that  the  antigen  in  the  Wassermaun  reaction  was 
non-specific,  and  that  its  place  could  be  taken  by  normal  tissue  extracts  and 
chemical  substances,  several  observers  conducted  experiments  with  the  extract  of 
a  guinea-pig's  heart,  with  lecithin,  sodium  glycocholate,  etc.,  but  all  were  with 
negative  results. 

After  Noguchi^  had  succeeded  in  culturing  the  Spirochaela  pallida,  he  prepared 
an  extract  of  the  growth  and  named  it  "'  luetin." 

Luetin,  mixed  with  an  equal  quantity  of  saline,  is  injected  into  the  skin — 
0'035  c.c.  luetin  and  0'035  c.c.  sahne. 

Noguchi  distinguishes  three  reactions  :  («)  the  papular  ;  (b)  the  pustular  ; 
(c)  the  torpid.     The  papular  form  is  most  commonly  seen  in  generalised  syphilis ; 

h2 


114  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SVPHILIS. 

the  pustular   form   is  seen   most  often   in    the  late  recurrent,  and  in   congenital 
cases. 

The  torpid  form  is  the  rarest,  and  is  recognised  by  the  fact  that  the  reaction 
does  not  appear  until  a  few  days  after  the  test  has  been  applied. 

Noguchi  found  that  in  untreated  cases,  in  both  the  primary  and  the  generalisa- 
tion stages,  the  luetin  reaction  was  usually  negative,  while  in  the  latent  stage,  and 
in  other  stages  in  which  treatment  had  been  given,  the  reaction  was  generally 
positive. 

In  cases  of  degenerative  encephalitis  and  degenerative  myelitis,  only  50  per 
cent,  gave  a  positive  reaction.  Other  American  observers® '  *  who  repeated 
Noguchi's  work,  obtained  similar  results. 

Noguchi  very  kindly  sent  me  some  material,  which  I  tried  on  several  cases. 
At  the  same  time  as  I  was  using  luetin,  I  was  also  experimenting  with  the  cutireaction 
obtained  with  various  specimens  of  gonococcal  vaccines.' 

In  early  cases  of  syphilis,  as  in  acute  cases  of  gonorrhoea,  whether  the  gono- 
coccus  was  limited  to  the  urethra  or  had  already  become  s)-stemic,  the  cutireaction 
was  generally  negative. 

In  late  cases  of  syphilis,  and  in  late  cases  of  gonorrhoea,  especially  when  there 
was  a  metastatic  complication,  the  reaction  was  ahnost  invariably  positive,  and 
often  very  markedly  so.  It  not  only  varied  in  intensity,  but  also  in  the  time 
which  elapsed,  between  giving  the  injection  and  the  onset  of  the  reaction.  If  a  test 
for  diagnosis  is  required  at  all,  it  is  most  necessary  in  the  early  stages  of  the  disease, 
when  cutireactions  are  usually  negative  ;  therefore,  as  a  means  of  helping  the 
practitioner  to  diagnose  a  sore,  the  luetin  reaction  must  not  be  relied  upon.  With 
luetin,  as  with  the  gonococcal  vaccines,  the  reaction  depends  not  only  upon  the 
strain  used,  but  largely  upon  the  experience  of  the  operator,  as  what  is  considered 
a  positive  reaction,  varies  with  almost  every  observer. 

It  is  important  to  note  that  a  positive  cutireaction  only  signifies  th^t  the 
patient  has  had  the  disease,  not  necessarily  that  he  still  has  it. 

Furthermore,  the  luetin  cutireaction  is  not  absolutely  specific,  as  I  have  been 
able  to  get  positive  reactions  in  patients  who  have  never  had  syphilis,  3  cases  in 
25  controls,  and  I  have  been  able  to  produce  a  positive  reaction  in  cases  of  syphilis, 
with  substances  other  than  luetin,  namely,  with  certain  hpoid-adsorption  complexes 
with  globulin. 

Boas  and  Ditlevsen^"  in  a  recent  article,  also  found  that  positive  reactions  were 
to  be  obtained  in  non-syphilitic  cases,  as  many  as  15  in  124. 

In  the  latent  and  recurrent  stages  of  sj^hilis,  although  the  luetin  reaction 
is  not  more  often  positive  than  the  Wassermann  reaction,  cases  are  to  be   met 


THE    CUTIREACTION.  115 

with,  in  which  the  former  is  positive  and  the  latter  negative,  and  vice  versa.  It 
has  been  suggested  that,  in  these  two  stages,  both  tests  should  be  applied,  but 
this  is  unnecessary,  as  such  cases  are  very  seldom  sources  of  infection  ;  a  clinical 
diagnosis  is  more  valuable  than  both,  and  a  positive  reaction  with  either  is  no 
certain  criterion  that  the  disease  is  active,  and  therefore  requires  treatment. 

A  peculiar  phenomenon  has  been  noted  by  Miiller  and  Stein^i,  and  Klausnei'i^, 
that  occasionally  a  case  of  late  recurrent  syphilis,  with  a  negative  Wassermann 
reaction  and  a  positive  cutireaction,  gave  a  positive  Wassermann  reaction  after  the 
cutaneous  test  had  been  applied. 

Owing  to  the  difficulty  experienced  in  cultivating  the  Spirochaeta  ■pallida,  the 
attention  of  a  few  observers  has  been  directed  back  to  the  tissue  extracts  ;  and 
now  the  lung,  from  cases  of  Pneumonia  alba,  is  the  organ  used.  Fischer,^'*  who 
was  the  first  to  use  lung  tissue,  prepared  his  extract  in  the  following  way  : — 

Pieces  of  lung  were  finely  broken  up  with  powdered  glass,  and  then  mixed 
with  an  equal  quantity  of  shghtly  alkaline  saline  solution.  The  mixture  was  then 
centrifuged,  and  the  fluid  obtained  was  heated  for  half  an  hour  at  60''  C.  To  keep 
the  fluid  sterile  carbolic  acid  was  added. 

The  control  solution  was  made  in  a  similar  way  with  healthy  lung  tissue. 

Of  each,  -^-4^  c.c.  was  injected  intracutaneously.  Fischer  himself  obtained 
negative  results,  but  Klausner,i'-  who  repeated  his  work  on  a  much  larger  scale, 
found  that  positive  results  were  the  rule,  in  recurrent  syphilis  and  congenital 
syphilis. 

In  1,200  control  cases,  the  reaction  was  always  negative.  In  primary  and 
generalised  syphilis,  the  reaction  was  also  usually  negative,  as  it  also  was  in  cases 
of  degenerative  myelitis  and  encephalitis  and  arterial  syphilis. 

Pallidin  is  the  name  which  has  been  given  to  this  lung  extract,  and  it  can  be 
obtained  from  Merck,  of  Darmstadt. 

It  would  not  be  out  of  place  now  to  discuss,  in  a  few  words,  the  rationale  or 
modus  operandi  of  this  reaction. 

I  do  not  think  it  is  necessary  to  mention  all  the  views  which  have  been 
expressed,  as  practically  each  one  has  entailed  the  necessity  of  coining  a  new  word, 
which  is  meaningless. 

So  far  as  syphilis  is  concerned,  two  important  points  come  to  light,  one  being 
that  the  cutireaction  is  only  of  value  in  the  late  cases  of  syphilis,  the  other  being  that 
occasionally  a  negative  Wassermann  reaction  is  converted  into  a  positive  reaction. 

The  histological  examination  of  lesions  produced  by  the  intradermal  injections 
of  syphilitic  extracts,  also  throws  considerable  light  upon  the  rationale  of  the  cuti- 
reaction. 


116  THE   BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   SYPHILIS. 

There  is,  first  of  all,  a  dilatation  of  the  vessels  and  Ipnphatics,  and  a  prohfera- 
tion  of  their  endothehal  cells.  These  endotheUal  cells  give  rise  to  ljTiiphoc}i:es, 
which  in  turn  develop  into  plasma  cells.     Others  become  giant  cells. 

The  lymphocytes  and  plasma  cells  form  the  protective  substance  of  the  host, 
and  this  protective  substance  is  a  specific  hpoid-globulin,  and  also  happens  to  be 
the  reagin  of  the  Wassermann  reaction. 

If  the  host  has  been  forming  this  protective  substance  for  two,  three,  or  more 
years,  there  comes  a  time  when  its  formation  becomes  continuous,  in  spite  of  the 
fact  that  all  the  parasites  have  been  vanquished.  Any  extra  call  upon  this  pro- 
tective substance  will  stimulate  the  production  of  this  specific  hpoid-globuUn. 
The  reply  to  the  stimulus  will  vary,  according  to  the  stage  at  which  it  is  appHed. 

Let  me  further  explain  this  point.  The  production  of  hpoid-globuhn,  as  stated 
above,  becomes  continuous,  but  always  in  an  increasing  ratio,  and  the  increasing 
ratio  is  greater  in  the  lipoid  than  in  the  globulin  portion  of  the  molecule. 

If  there  is  to  be  an  ever-increasing  amount  of  lipoid-globuhn  formed,  there 
must  of  necessity  be  a  corresponding  increase  of  cells  formed,  to  produce  it. 

Should  the  parasitic  Upoid-globuhn  be  introduced  into  the  host,  as  is  the  case 
when  the  syphilitic  extract  is  injected  intracutaneously,  the  production  on  the 
part  of  the  host  of  a  lipoid-globulin  which  has  the  same  stereo-chemical  molecular 
configuration  as  that  of  the  parasitic  lipoid-globulin,  will  vary  according  to  the 
stage  of  productive  mechanism  in  which  the  host  is. 

If  the  productive  mechanism  of  the  host  is  at  or  near  its  zenith,  it  will  follow 
that  any  extra  call  upon  it  will  meet  with  the  greatest  response.  This  means  that 
the  greatest  number  of  endothehal  cells,  lymphocytes  and  plasma  cells  will  be 
formed.  The  reaction  will  be  very  marked.  The  greater  the  reaction,  the  more 
likehhood  there  will  be  of  the  vessels  being  occluded.  Occlusion  of  vessels  means 
loss  of  blood  supply  to  that  area  of  sldn  supplied  by  them.  Therefore,  the  greater 
the  reaction,  the  more  the  lesion  will  resemble  a  gmnma.  Syphilitic  cutireactions 
simulate  syphihtic  lesions.  The  lesion  of  a  mild  reaction  resembles  a  papule  ;  the 
lesion  of  a  severe  reaction  resembles  a  gumma.  No  lesion  can  resemble  a  chancre, 
because  such  a  lesion  can  only  be  produced  when  the  host  does  not  elaborate  the 
specific  lipoid-protein,  and,  when  the  host  does  not  manufacture  this  substance, 
a  positive  cutireaction  cannot  be  obtained. 

Broadly  speaking,  no  negative  reaction  is  of  value,  therefore  onh^  a  final  word 
need  be  said  about  the  positiye  cutireaction. 

As  the  host  persists  in  manufacturing  the  specific  lipoid-globulin  substance, 
in  spite  of  the  fact  that  there  are  no  organisms  to  Icill,  it  will  follow  that  when  the 
homologous  parasitic  lipoid-globulin  is  injected,  a  reaction  will  result,  but  this  does 


THE    CCTIREACTIOX.  117 

not  mean  that  the  patient  is  suffering  from  s}-j)hilis  ;  it  means  only  that  the  pro- 
babihty  exists  that  he  has  had  the  disease. 

Although  tuberculin  does  not,  as  a  rule,  give  a  cutireaction  in  cases  of  syphilis, 
it  is  an  odd  fact  that  the  inflammation  produced  by  an  injection  of  tuberculin,  in  a 
syphilitic  case,  is  very  much  increased,  if  an  injection  of  pallidin  is  given  afterwards, 
and  vice  versa. 

This  interesting  observation  has  been  made  by  several  workers  (Klausner,^- 
Kammerer,^*  Nogirchi,^  Meirowsky'-),  but  each  has  put  his  own  interpretation 
upon  it. 

The  simplest  explanation  appears  to  me  to  be  the  following  : — 

The  tubercle  bacillus,  and  hence  tuberculin,  have  their  own  specific  lipoid- 
globuhn,  and  the  host  upon  which  they  are  implanted  elaborates  a  hpc.^d-globulin 
which  has  the  same  stereo-chemical  molecular  configuration  as  that  of  the  parasite. 

The  specificity  of  the  lipoid-globnlin  does  not  he  in  the  lipoid-globuhn,  as 
such,  but  in  the  polypeptide  molecules  upon  which  it  is  built  up. 

The  same  applies  to  the  specific  s^'philitic  lipoid-globulin. 

The  different  physical  molecular  configurations  of  these  groundwork  stones 
(polypeptides),  upon  which  other  stones  are  laid,  until  the  house  (lipoid-globulin) 
is  complete,  must  be  very  slight,  and  in  many  cases  no  doubt  man}'  of  the  stones  are 
identical.  Supposing  then  that  some  of  the  gi'oundwork  molecules  in  the  syphilitic 
lipoid-globulin  were  the  same  as  those  in  the  tubercular  hpoid-globulin,  an  injection 
of  the  one  would  increase  the  reaction  of  the  other,  if  it  had  been  previously 
injected,  and  vice  versa. 

Although  every  parasite  elicits  the  production  by  the  host  of  a  specific  lipoid- 
globuhn,  the  manner  in  which  these  specific  lipoid-globnlins  are  built  up  is  in  some 
cases  partially  identical.  Hence,  when  a  crude  measure  like  the  intracutaneous 
injection  is  adopted,  or  when  we  have  a  still  cruder  method  in  the  Wassermann 
reaction,  for  testing  for  these  specific  proteins,  it  will  follow  that  slightly  positive 
results  will  occur  in  other  conditions,  so  we  niay  call  them  group  reactions. 

An  instance  of  a  group  reaction  in  the  cuti-test  is  seen  in  the  above  ;  and  in 
the  Wassermann  reaction  we  have  the  positive  results  given  by  malaria,  sleeping 
sickness,  yaws,  and  leprosy.  , 

If  a  few  injections  of  a  syphilitic  extract  are  given  to  a  patient  who  has  not 
had  syphilis,  time  allowed  to  elapse,  and  then  another  injection  is  given,  a  positive 
reaction  will  be  obtained.  This  has  long  been  known  to  be  the  case  with  tubercuhn. 
Such  a  reaction  is  called  an  anaphylactic  reaction. 

From  what  has  been  stated  in  this  chapter,  the  rationale  of  this  phenomenon 
should  be  quite  clear. 


118  THE    BIOLOGY,    CLINICAL    ASPECT   AND   TREATMENT   OF   SYPHILIS. 

Several  injections  of  a  syphilitic  extract  lead  to  the  formation  of  an  homologous 
lipoid-globuhn.  Provided  neither  too  short  nor  too  long  an  interval  is  allowed  to 
elapse,  a  further  injection  will  give  rise  to  a  reaction,  owing  to  the  fact  that  the 
memory  of  the  formation  of  the  specific  Hpoid-globulin  remains,  with  the  result 
that  an  increased  production  of  the  protective  substance  is  brought  forward  in 
response  to  the  stimulus. 

>  Tedeschi  (1908),  '•  Gaz.  degli  Osped.,"  xxix,  620. 

2  Meirowsky  (1911),  Xeisser'.s  "  Beitriige  zijr  Path.  u.  Ther.  der  Syphilis." 

3  Ciuflfo  (1909),  "  Gaz.  degU  Osped,"  xxx,  81.3. 

*  Nicolas,  Favre,  Gautier  et  Charlet  (1910),  "  Lyon  Med.,"  cxiv,  621. 

5  Noguchi  (1911),  ".Journ.  of  Exper.  Med.,"  xiii,  43,  7S,  217. 

'  Robinson  (1912),  "Journ.  of  Cutan.  Dis.,"  xxx,  410. 

'  Fox  (1912),  "Journ.  of  Cutan.  Dis.,"  xxx,  465. 

8  Wolfsohn  (1912),  "  BuU.  of  the  Johns  Hopkins  Hosp.,"  xxiii,  223. 

»  McDonagh  and  Klein  (1913),  "  Journ.  of  Path,  and  Bact.,"  xvii,  599. 

'"  Boas  u.  Ditlev.sen  (1913),  "  Archiv.  fiir  Derm.  u.  Syph.,"  cxvi,  853. 

"  MuUer  u.  Stein  (1913),  "  Wien.  med.  Woch.,"  Ixiii,  2419,  2614. 

'2  Klausner  (1914),  "  Archiv.  f.  Derm.  u.  Syph.,"  cxs,  444. 

"  Fischer  u.  Klausner  (1913),  "  Wien.  klin.  Woch.,"  xxvi,  49. 

"  Kiimmerer  (1912),  "  Munch,  med.  Woch.,"  lix,  1534. 


CHAPTER   XIII. 
THE   BIOLOGY   OF   THE   VARIOUS   STAGES   OF    SYPHILIS. 

The  Primary  Stage. 

After  a  patient  has  exposed  himself  to  infection,  one  or  more  spores  gain 
access  to  the  skin,  in  which  they  develop.  When  sufficient  cycles,  which  comprise 
the  life  history  of  the  Leucoojtozoon  si/pJulidis,  have  been  completed,  the  patient 
develops  a  sore.  As  the  host  cannot  immediatelj^  form  protective  bodies,  there  is 
no  limit  to  the  number  of  sores  which  may  be  present,  the  number  depending  upon 
the  different  points  of  entrance  of  the  organism.  In,  roughly,  30  per  cent,  of 
cases  of  syphilis,  there  is  more  than  one  primary  sore,  the  most  I  have  ever  seen 
being  eighteen. 

When  the  spore  has  entered  the  body,  it  seeks  out  a  connective-tissue  cell, 
or  an  endothelial  cell,  to  the  protoplasm  of  which  it  gains  access.  Therefore, 
the  connective-tissue  cell,  and  the  endothelial  cell,  are  the  first  cells  to  be  attacked 
in  sj-philis,  consequently  the  brunt  of  the  attack,  and  the  resistance  offered,  will 
affect  these  cells,  with  the  result  that  there  will  be  marked  multiplication  of 
them. 

Connective-tissue  cells  later  become  fibrous  tissue,  hence  the  explanation  of 
the  so-called  induration  of  chancres.  The  induration  is  purely  relative,  since  a 
sore  may  appear  before  the  connective-tissue  cells  have  had  time  to  form  fibrous 
tissue,  or  a  sore  may  develop  in  loose  tissue,  in  which,  if  fibrous  tis.sue  did  form, 
it  would  be  scarcely  noticed ;  or  the  endothelial  cell  may  be  the  main  cell  attacked, 
in  which  case  there  is  practically  no  proliferation  of  the  fixed  connective-tissue 
cells.  Furthermore,  in  those  cases  in  which  only  the  asexual  stage  is  perpetuated, 
the  endothelial  cells  are  the  cells  most  involved,  hence  the  type  of  sore  formed 
is  never  indurated. 

As  a  sore  may  appear  before  there  is  any  induration,  it  follows  that  the  in- 
cubation period  of  syphilis  must  vary  somewhat,  as  it  does — from  eight  days  to  six 
weeks,  or  more.     As  the  connective-tissue  cells  and  the  endothelial  cells  are  first 


120  THE    BIOLOGY,    CLINICAL    ASPECT    AND    TREATMENT   OF    SYPHILIS. 

attacked,  there  will  be  no  great  call  upon  leucocytes,  and  as,  in  my  opinion, 
phagocytosis  plays  no  part  at  all  in  protozoal  infections,  there  will  be  no  pus  and 
no  necrosis.  Therefore,  if  a  sore  occurs,  it  will  be  an  erosion,  and  not  an  ulcer. 
Occasionally  a  chancre  is  to  be  met  with,  in  which  the  surface  epithelium  never 
breaks.  In  the  sore  formed  by  the  asexual  development  of  the  Leucocytozoon 
syphilidis,  owing  to  the  manner  in  which  the  endothelial  cell  is  attacked,  and 
its  consequent  multiplication,  vessels  become  occluded.  This  occlusion  results 
in  necrosis  of  the  skin  above,  hence  such  a  primary  sore,  is  an  ulcer  from 
the  start. 

As  a  primary  sore  most  usually  affects  regions  which  are  swarming  with 
saprophytic  organisms,  it  may  easily  become  infected  or  even  phagedaenic  ;  then, 
instead  of  a  simple  erosion,  there  may  be  a  big  ulcer. 

If  the  saprophytic  organisms  attack  the  sore  early  enough,  and  if  they  are 
particularly  active,  they  may  succeed  in  annihilating  the  leucocytozoon.  This 
explains  why  some  phagedaenic  sores  are  not  followed  later  b)'  further  evidences  of 
syphilis.  In  any  case,  the  onset  of  phagedaena  alters  the  sequence  of  the  disease, 
usually  by  delaying  the  outbreak  of  the  rash,  sore  throat,  etc. 

In  this  observation  I  see  the  indication  for  removing  a  primary  sore,  when 
possible,  or  for  cauterising  those  that  cannot  be  so  handled. 

In  comparing  the  primary  sore  of  human  syphilis  with  that  of  experimental 
syphihs,  one  is  at  once  struck  by  the  great  tendency  to  ulcerate  exhibited  by  the 
latter.  Moreover,  the  experimental  sore  is  always  clinically  the  same,  while  the 
sore  of  human  syphihs  may  show  numerous  clinical  varieties. 

A  human  chancre  is  generally  an  erosion  and  not  an  ulceration  (the  asexual 
sore  excepted) ;    the  experimental  sore  is  always  an  ulceration. 

From  this  simple  chnical  difference  between  ordinary  and  experimental 
syphilis,  and  from  the  hght  which  has  already  been  thrown  upon  the  causative 
agent  of  the  disease,  it  may  be  assumed  that,  as  the  lesions  of  experimental  syphihs 
never  vary,  only  one  portion  of  the  life-cycle  of  the  specific  organism  develops. 
Since  spirochaetae  are  found  in  greater  abundance  in  experimental  chancres  than 
in  ordinary  chancres,  and  since  the  long  angulated  forms  are  frequently  to 
be  met  with,  it  is  possible  that  only  the  extracellular  development  of  the  male 
body  occurs. 

The  spirochaetae  obtained  from  experimental  chancres  are  tj'pical  of  those 
grown  in  culture,  and  those  I  have  found  in  the  brain,  from  cases  of  degenerative 
encephalitis.  Therefore,  it  will  now  be  seen  that  my  earlier  remark — "  What 
is  happening  in  the  test  animal's  body  may  be  no  more  than  is  taking  place  in  a 
culture  tube  " — is  possibly  near  the  truth.     In  rabbits,  after  the  primary  sore  has 


THE    BIOLOGY   OF   THE    VARIOUS    STAGES    OF   SYPHILIS.  121 

existed  for  a  little  time,  the  inguinal  Ipuphatic  glands  become  enlarged,  and  the 
virus  becomes  generalised  in  the  system.  According  to  Graetz  and  Delbanco  it  is 
extremely  rare  for  any  histological  changes  to  be  found  in  the  inguinal  lymphatic 
glands,  and  often  spirochaetae  cannot  be  demonstrated.  To  prove  that  the  virus 
is  undoubtedly  harbouring  in  them,  it  was  found  necessary  to  inoculate  another 
animal  with  part  of  the  lymphatic  gland. 

Comparing  this  with  human  syphihs,  again  great  difEerences  arise.  Broadly 
speaking,  the  smaller  the  lymphatic  gland,  the  more  marked  are  the  histological 
changes  found  therein.  Many  of  the  small  lymphatic  glands  which  I  have 
examined,  are  crowded  with  giant  cells  and  small  areas  of  necrosis,  exactly  resembling 
a  tuberculous  lymphatic  gland.  The  cells  in  the  small  lymphatic  glands  are 
mainly  endothelial  cells,  a  few  lymphocytes  may  be  found,  and  only  a  very  small 
number  of  plasma  cells,  showing  that  the  resistance  of  the  host  is  feeble,  and  that 
its  last  line  of  support  has  been  attacked.  To  understand  the  full  significance 
of  this  remark,  the  reader  must  be  referred  to  Chapter  XLVI. 

The  large  glands  also  show  marked  changes,  but,  instead  of  consisting  mainly 
of  endothelial  cells,  they  are  crammed  with  plasma  cells.  It  is  not  difficult  to 
find  spirochaetae  in  the  inguinal  glands  removed  from  human  syphilis. 

Tissue,  which  when  inoculated  into  animals  gives  rise  to  lesions  from  which 
spirochaetae  can  be  obtained,  need  not  necessarily  contain  spirochaetae,  etc. 
Therefore,  when  the  organisms  are  found  in  the  fresh  lesion,  it  is  no  proof  that  the 
tissue  which  gave  rise  to  that  lesion  harboured  spirochaetae.  All  that  can  be  said 
is,  that  the  tissue  in  question  contained  spores,  which  were  capable  of  giving  rise 
to  spirochaetae  when  inoculated.  As  I  have  frequently  been  able  to  demonstrate, 
spores  of  the  Leucocytozoon  syphilidis  do  not  give  rise  to  inflammation,  and  therefore 
the  histological  structure  of  any  tissue  in  which  they  are  present  may  remain 
unaltered.  The  phase  which  causes  the  greatest  histological  change  is  that  of  the 
SpirocJiaeta  pallida,  the  adult  male  form. 

It  must  be  noted  how  frequently  animals  which  have  been  inoculated  with 
syphilitic  material,  fail  to  develop  even  an  initial  lesion.  It  is  doubtful  whether 
a  single  human  being  would  escape  under  similar  circumstances.  The  quantity 
of  material  that  is  usually  required  to  infect  the  animal  should  also  be  taken  into 
consideration  ;  it  would  be  equivalent  to  giving  a  hmnan  being  a  few  ounces  of  the 
infective  material. 

Therefore,  it  is  not  surprising  that  an  infection  arises,  or  rather  what  is  taken 
for  an  infection.  I  have  recently  discovered,  that  in  some  of  the  human  ulcerative 
chancres,  the  spirochaetae  develop  extra  cellularly  (Plate  31). 


122  the  biology,  clinical  aspect  and  treatment  of  syphilis. 

Other  Stages. 

At  a  varying  interval  after  the  sore,  a  lymphangitis  and  enlargement  of  the 
lymphatic  glands  occur,  and  this  is  part  of  the  host's  protective  machine,  and  is 
for  the  purpose  of  elaborating  lymphocytes  to  attack  the  infection.  The  enlarge- 
ment of  tlie  lymphatic  glands  bears  no  ratio  to  the  severity  of  the  disease.  On  the 
contrary,  it  bears  a  ratio  to  the  protective  capacity  of  the  host ;  hence  big  glands 
are  not  the  best  to  choose,  in  which  to  hunt  for  the  organisms  ;  it  is  in  the  small 
glands  that  most  are  to  be  found. 

Glands  should  be  looked  upon  as  the  base  on  the  field  of  operation,  and  there- 
fore should  not  be  removed,  as  has  of  late  been  advised. 

Another  point  in  favour  of  my  view,  that  phagedaena  kills  the  syphihtic 
organism,  is  the  fact  that  most  phagedaenic  chancres  are  not  accompanied  by  either 
a  lymphangitis  or  by  an  enlargement  of  the  nearest  chain  of  lymphatic  glands  ; 
oddly  enough,  not  even  the  secondary  infection  causes  them  to  become  enlarged. 
The  reason  of  this  is,  that  when  a  chancre  becomes  phagedaenic,  the  secondary 
infection  is  not  a  staphylococcic  or  streptococcic  infection,  but  an  infection  due 
to  the  fusiform  bacillus  and  the  Gram  negative  spirochaeta,  which  live  in  symbiosis. 
The  glandular  enlargement  following  this  infection  is  minimal. 

From  the  nearest  chain  of  lymphatic  glands,  the  organisms  spread  along  the 
lymphatics,  until  other  chains,  and,  ultimately,  all  the  lymphatic  glands  in  the 
body,  are  infected.  While  the  lymphatic  extension  is  proceeding,  the  organisms 
are  also  pervading  every  nook  and  crevice  in  the  body  by  means  of  the  blood- 
stream.    In  this  way,  the  generalisation  symptoms  arise. 

The  symptoms  will  eventually  disappear  without  treatment,  but  their  dis- 
appearance is  hastened  by  the  administration  of  mercury,  which  works  slowly, 
or  of  salvarsan,  which  works  almost  instantaneously. 

The  action  of  treatment  is  primarily  to  destroy  the  spirochaetae,  whiclj  are 
mainly  responsible  for  the  symptoms.  The  other  phases  are  destroyed  secondarily 
and  indirectly.  As  the  spirochaetae  are  mainly  responsible  for  the  lesions,  the 
protective  mechanism  of  the  host  will  be  especially  directed  against  these  bodies, 
but  their  death  does  not  mean  that  the  spores  are  destroyed. 

If  no  treatment  is  given,  or  if  mercury  alone  is  prescribed,  the  spirochaetae 
will  vanish  for  a  time.  The  spores,  as  they  seek  fresh  hunting-ground,  will  spread 
peripherally,  so  that  when  symptoms  recur,  the  lesions  will  be  in  the  form  of  circles 
or  segments  of  circles.  When  no  symptoms  are  visible,  the  patient  is  said  to  be 
in  the  latent  stage,  and  when  symptoms  reappear  again,  he  is  said  to  be  in  the 
recurrent  stage. 


THE    BIOLOGY    OF   THE    VARIOUS    STAGES   OF   SYPHILIS.  123 

If  salvarsan  is  prescribed,  tlie  spirochaetae  are  destroyed  at  once  ;  the  spores 
are  crippled  temporarily  in  situ,  so  that  when  they  start  their  life-cycle  again,  it 
will  take  place  in  the  same  positions  ;  hence  the  reason  why  recurrences  after 
salvarsan  simulate  the  lesions  for  which  salvarsan  was  given. 

The  early  lesions  of  syphilis  are  more  infectious  than  the  recurrent  ones. 
Therefore,  insufficient  use  of  salvarsan,  or  the  failure  to  supplement  its  administra- 
tion with  mercury,  may  do  more  harm  than  good,  in  that  the  infectious  period  may 
be  thereby  lengthened. 

I  have  seen  ten  cases  in  which  the  wife  was  infected  by  her  husband,  who  had 
been  told  that  he  was  cured  after  he  had  had  two  injections  of  salvarsan. 

In  view  of  what  has  been  stated,  and  for  reasons,  which  will  be  given  later, 
I  feel  that  I  am  justified  in  advising,  as  has  been  my  practice  for  over  three  years, 
several  injections  of  salvarsan,  given  as  close  upon  one  another  as  possible,  to  be 
followed  by  at  least  one  year's  treatment  with  mercury. 

The  longer  the  spores  are  present  in  any  one  spot,  the  more  chronic  inflam- 
matory changes  will  the  local  vessels  exhibit.  Hence,  should  a  lesion  occur,  it  will 
lead  to  still  further  trouble,  even  to  obliterative  endarteritis,  which  will  result  in 
necrosis  of  the  skin  over  the  area  fed  by  the  affected  artery  and  the  formation  of 
a  gumma. 

A  gumma  occurs  mechanically,  and  the  necrosis  is  not  due  directly  to  the 
specific  organisms.  In  the  necrosis,  saprophytic  organisms  flourish,  and  they  at 
once  kill  the  leucocytozoon,  with  the  result  that  the  secretion  therefrom  is,  to  all 
intents  and  purposes,  non-infectious.  The  specific  organism  lives  in  the  tissue 
surrounding  the  necrosis. 

As  the  endothelial  cell  is  frequently  the  cell  upon  which  the  Leucocytozoon 
syphilidis  is  parasitic  it  will  be  readily  understood  why  vascular  lesions  are  so 
common  in  syphilis. 

The  biology  of  syphilis  in  women  will  be  considered  in  another  chapter,  and 
likewise  the  biology  of  syphilis  of  the  central  nervous  system. 


CHAPTER  XIV. 
THE   CLINICAL  ASPECT   OF   THE   SYPHILITIC   CUTANEOUS   LESIONS. 

A  writteu  description  of  the  cutaneous  .syphilitic  lesions  may  give  a  little 
help  in  diagnosing  them,  when  seen.  It  must,  however,  be  remembered  that, 
the  only  way  in  which  anyone  can  obtain  a  good  clinical  knowledge  of  the  skin 
manifestations,  is  by  careful  study  of  as  many  cases  as  possible.  This  especially 
applies  to  the  chancre. 

Everyone  is  agreed  that,  if  syphilis  is  to  be  lessened,  diagnosis  of  the  initial 
lesion  at  the  earliest  possible  moment  is  essential.  I  feel  very  strongly  that  the 
best  diagnosis  is  a  clinical,  and  not  a  bacteriological  one.  Therefore,  it  behoves 
the  whole  medical  profession  to  make  themselves  au  fait  with  the  clinical  methods 
of  diagnosing  early  sj'philis,  and  to  see  that  the  future  generation  is  thoroughly 
taught  such  methods. 

Chancre. 

A  primary  sore  may  occm-  on  any  part  of  the  body,  but,  for  sake  of  convenience, 
primary  sores  may  be  divided  into  genital  and  extragenital  sores.  In  most 
countries  the  syphilitic  infection  is  genital  in  origin,  but  in  some  districts,  where 
the  people  are  very  poor,  uncleanly,  and  many  live  together  in  one  room,  the 
infection  is  more  often  extragenital.  In  certain  parts  of  South-Eastern  Europe, 
the  ratio  between  extragenital  and  genital  sores  may  be  as  high  as  twenty  to  one. 

Four  main  points  are  usually  sought  for  in  diagnosing  a  sore.  The  sore  must 
be  single,  it  must  be  indm-ated,  it  must  not  appear  for  from  four  to  six  weeks  after 
connection,  and  the  l}Tnphatic  glands  in  the  groin  must  be  enlarged  and  hard. 

Let  us  take  each  of  these  points  in  turn,  and  see  how  far  they  are  of  value 
in  assisting  one  to  make  a  diagnosis  in  a  difficult  case.  In  about  30  per  cent,  of 
cases  of  syphilis,  there  is  more  than  one  primary  sore,  when  the  infection  is  a 
genital  one.  When  extragenital,  the  sore  is  almost  invariably  single.  A  soft 
sore,  which  appears  in  the  minds  of  most  to  be  the  only  sore,  which  has  to  be  dis- 
tinguished from  a  primary  sore,  is  also  sometimes  single,  especially  if  it  be  seen 
early,  or  is  of  the  "  elevatum  "  type. 


Plate  25. — Papulo-erosive  Chancre. 


It  should  be  noted  that  the  lesion  is  sharply  circumscribed,  perfectly 
regular  in  outline,  that  it  is  raised  above  the  surrounding  tissue,  that  there 
is  very  little  loss  of  surface,  and  that  there  is  not  a  trace  of  circumferential 
inflammation.     The  patient  had  two  similar  sores  on  the  opposite  side. 

Spirochaetae  can  always  be  found  in  this  type  of  sore  and  the  micro- 
scopic appearance  of  the  lesion  is  characteristic.  There  is  a  marked  hyper- 
plasia of  the  connective-tissue  cells ;  the  walls  of  the  vessels  are  thickened, 
and  the  endothelial  cells  are  increased  in  number.  There  are  few  leucocytes, 
and  those  present  are  nearly  all  plasma  cells  ;  the  others  are  lymphocytes, 
but  there  are  no  polymorphonuclear  leucocytes.  The  section  is  crowded 
with  all  the  phases  of  the  Leucorytozoon  syphilidis.  This  is  the  type  of  sore 
which  gives  rise  to  the  severest  cases  of  syphilis. 


Facing  p.  124. 


M'lv  (it  as  I'vir.y  cases  ;is  p-. 
aaoKAHO  avieoaia-CMcraA*! — .5S  aTAal 

i(;rtu9ho(}  J)oiIiTj2uiojiiv  '{tqir.ris  ai  noiaoE  arii  Itsd)  hoJoii  'xl  bluoti^.  i\ 
modi  isiii  ,'Ji/8Bit  gntbrtijonua  orii  ovoffs  bagiBi  at  Ji  iBilt  .oriildijo  ni  ibIu^'h 
Ix>iifi9i9irau9iio  lo  ooBTt  «  Joa  Bi  onari*  JbiII  fans  .eaahua  io  eeof  oliiil  yiav  si 
.sbig  oJieoqqo  oxfJ  no  aaioB  lefiniie  oiii  bmi  Inoiiaq  otlT     .norj/imrruiftrii 
-oioiin  orit  biiB  o'loa  lo  oq\(t  airiJ   ni  btrool  ad  8v«'wl6  hbo  9BlojBi(ooiiq8 
-loqvil  bojfiBfn  B  ai  r>i3dT     .oi JaiiatooiBrio  ai  noia^I  edi  16  oonBij>o(£qB  yiqb'w    ' 
.bangdolrit  oib  afoaaav  orij  lo  sIIbv/  oHJ    ;  alloa  on«aii-9vidoonnoo  oriJ  lo  Biwulq 
.aoiijoooijol  nai  me  9i8riT     noclmon  ni  fasajsoiofii  9tb  alleo  [filodjobns  odi  bn^ 
.aai'^ooriqmvf  otb  eiedlo  9dl    ;  alloa  BoiaBlq  Ifu  i^hean  9i£  .Jn989Tq  98od*  bn* 
hsbffoio  ai  noi}o9a  9dT     .aot^ooouol  iBelai/nndqioflr^roq  on  oib  m'sdi  iiid  ' 
oioa  lo  oqyt  adi  si  aidT     .?»V>'iSW(\^?.  «oos<>\^ior>»9A  adt  loBoaedq  od)  il«  dJiW' 

.ailidq'ja  lo  Sfiaeo  if/jnyoa  ndi  ot  fwli  Kf)/i<!  d  lid// 


.HI  .n  v'»»»'^ 


x*^-. 


Plate  25. 


SYPHILIS   OF   THE    SKIN.  125 

Indui'ation,  when  present,  may  be  valuable  as  a  proof  of  syphilis,  but  its 
absence  by  no  means  negatives  syphilis.  Induration  is,  in  part,  a  process  of  healing, 
consequently  if  patients  are  to  be  urged  to  seek  advice,  the  moment  they  notice 
a  sore,  the  value  to  be  placed  upon  induration  as  a  diagnostic  sign  will  be  considerably 
diminished.  A  chancre,  as  a  rule,  becomes  most  indurated  when  it  is  about  to 
disappear,  consequently,  if  the  sore  is  indurated  when  the  patient  seeks  advice, 
the  chances  are  greatly  in  favour  of  the  generalisation  stage  having  already  started. 
Many  sores  heal  and  vanish  without  ever  becoming  indurated. 

The  sore  must  not  appear  for  from  four  to  six  weeks  after  connection.  Those 
who  wish  to  diagnose  a  sore  correctly,  wull  be  well  advised  never  to  ask  how  soon 
after  connection  a  sore  appeared.  In  the  first  place,  the  period  of  incubation  varies 
from  eight  to  sixty  days  ;  in  the  second  place,  many  men  have  connection  once 
a  week,  and  the  chances  are  that  they  will  blame  the  woman  with  whom  they  last 
had  intercourse. 

The  l}Tnphatic  glands  in  the  groin  must  be  enlarged  and  hard.  In  about 
5  per  cent,  of  cases,  no  palpable  change  in  the  lymphatic  glands  can  be  ascer- 
tained. In  many  cases,  it  is  impossible  to  distinguish  an  enlargement  due  to 
syphilis  from  an  enlargement  caused  by  any  other  venereal  disease  ;  for  instance, 
in  about  90  per  cent,  of  all  cases  of  acute  gonorrhoea,  the  inguinal  Ivmphatic  glands 
are  enlarged.  Hardness,  if  present,  is  characteristic  of  syphilis,  but  it  means  that 
the  patient  has  passed  into  the  generalisation  stage — indeed  almost  any  change 
in  the  lymphatic  glands  signifies  that  the  disease  has  become  generahsed.  If 
cases  are  to  be  diagnosed  much  earlier  than  is  now  the  case,  palpation  of  the 
inguinal  regions  will  give  little  or  no  clue  as  to  the  nature  of  the  sore. 

If  there  is  still  any  doubt,  resort  is  had  to  a  bacteriological  examination.  If 
the  SpirocJiaeta  pallidal  is  found,  it  is  a  proof  that  the  sore  is  syphihtic,  but  if  the 
organism  is  not  found,  it  is  no  proof  that  the  sore  is  not  syphihtic.  In  many  syphilitic 
sores,  very  few  spirochaetae  exist,  and  therefore  they  may  easily  be  missed  ;  in  a 
few  syphilitic  sores,  the  spirochaetal  stage  is  never  reached  ;  therefore,  however 
careful  the  search  may  be,  no  spirochaetae  will  be  foimd.  In  quite  a  large 
percentage  of  cases,  when  the  sore  is  in  the  corona,  and  the  patient  has  a  phimosis, 
it  is  impossible  to  reach  the  sore,  far  less  to  obtain  a  scraping  from  it. 

If  any  observer  would  examine  bacteriologically  100  consecutive  doubtful 
sores,  which,  to  a  trained  cHnical  eye,  were  considered  to  be  syphilitic,  he  would 
be  very  much  surprised  and  chagrined  at  the  comparatively  large  percentage  of 
cases  in  which  he  failed  to  find  the  Sjnrochaeta  pallida.  It  is  in  just  this  type  of 
sore  that  an  inexperienced  clinician  is  most  dependent  upon  the  finding  of  the 
bacteriologist. 


126  THE    BIOLOGY,    CLINICAL    ASPECT   AND   TREATMENT   OF   SYPHILIS. 

There  is  only  one  certain  way  of  diagnosing  a  sore,  and  that  is  by  looking  at 
it.  I  will  endeavour,  in  the  following  lines,  to  put  into  words  the  mental  pictures 
which  I  have  of  the  various  sores,  but  I  must  warn  the  reader  that  were  these  pictures 
ever  so  faithfully  portrayed,  they  would  never  adequately  take  the  place  of  a  few 
visits  to  a  hospital  for  venereal  diseases. 

The  spore  of  the  Leticocytozoon  syphilidis  is  the  infective  agent  of  s}'philis. 
When  the  spore  gains  entrance  to  a  new  host,  it  develops  at  the  expense  of  the 
endothehal  and  connective-tissue  cells.  At  first  it  produces  little  or  no  change  in 
the  host's  protective  cells,  consequently,  the  incubation  period  of  a  syphilitic  sore 
is  a  comparatively  long  one,  but  naturally  it  is  dependent  upon  how  the  parasite 
develops,  as  its  modes  of  development  are  various.  If  the  Leucocytozoon  syphilidis 
develops  into  male  and  female  bodies,  and  it  does  so,  in  most  cases,  the  host  will 
increase  the  production  of  his  protective  cells,  as  the  male  and  female  bodies  cause 
the  greatest  reaction.  The  more  protective  cells  that  are  formed,  the  more  swollen 
will  the  lesion  be,  the  epithelium  is  raised,  and  the  tissue  beneath  the  corimn  is 
depressed.  Such  a  lesion  is  a  papule.  As  more  sexual  bodies  are  formed,  and 
more  plasma  cells  and  lymphoc}i;es  are  turned  out,  the  connective-tissue  cells 
rapidly  increase,  and  so  do  the  endothelial  cells.  Now,  every  one  of  these  facts 
must  have  an  influence  upon  the  blood  or  lymphatic  supply  to  the  epithelium 
directly  above,  with  the  result  that  any  external  friction  will  be  just  sufficient  to 
injure  it  further,  so  that  it  is  rubbed  oH.     The  lesion  is  now  an  erosion. 

If  the  proliferation  of  the  connective-tissue  and  endothehal  cells  persists,  the 
fluid  or  nutritive  supply  to  the  tissue  above  will  be  cut  off,  •«"ith  the  result  that  it 
will  necrose.     The  lesion  is  now  an  ulcer. 

When  necrosis  occurs,  a  secondary  infection  is  very  liable  to  supervene, 
especially  if  the  sore  is  nicely  tucked  away  under  a  tight  fore-skin.  The  secondary 
infection  is  usually  caused  by  the  Gram  negative  spirochaeta  and  the  Gram  positive 
fusiform  bacillus,  two  organisms  which  will  live  in  STOibiosis,  and  which  flourish 
well  under  anaerobic  conditions.     The  lesion  is  now  a  phagedaenic  ulcer.      ■> 

The  process  may  stop  at  any  one  of  the  stages  just  mentioned.  A  primary  sore 
may  never  be  more  than  a  papule.  Most  primary  sores  are  simple  erosions,  but 
many  primary  sores  are  markedly  indurated  before  any  ulceration  occurs. 

With  the  exception  of  the  sore  that  becomes  secondarily  infected,  there  is 
no  increase  of  polymorphonuclear  leucocytes,  because  phagocytosis  plays  no  part 
in  the  destruction  of  the  syphilitic  parasite,  hence  there  is  no  pus,  and  the  necrosis 
which  occurs  is  a  mechanical  necrosis,  and  is  not  due  to  the  presence  of  several 
polymorphonuclear  leucocj'tes  which  cause  necrosis  owing  to  their  proteolytic  action. 
Therefore,  the  necrosis  of  a  syphilitic  sore,  not  secondarily  infected,  is  a  dry  necrosis. 


Plate  26. — Papulo-eeosive  Chancre  on  the  Skin  of  the  Penis. 


I'l.A 


Facing  p.  126. 


^VAifi  HUT  to  Kia?!  -anT  vio  aaoKAHO  aviP.oaa-ojaiA? — .<i2  3T/j'1 


'JasWyi-liJi" 


Plate  20. 


^  SYPHILIS    OF  THE    SKIN.  127 

As  the  loss  of  surface  of  a  syphilitic  sore  occurs  more  or  less  mechanically,  it 
will  naturally  follow  that  the  loss  of  surface  will  exactly  correspond  with  the  area 
of  the  cellular  infiltration  in  the  corium  which  is,  by  its  pressure,  shutting  ofJ  the 
nutiition  from  the  tissue  above.  Consequently,  the  loss  of  surface  will  be  circular, 
and  circumscribed.  As  the  host  soon  begins  to  protect  himself  against  the  parasite, 
and  as  there  are  no  phagocytic  cells  present  which  have  a  proteolytic  action,  it  will 
follow  that  the  sore  will  neither  increase  in  size,  nor  will  there  be  any  ragged  edge, 
nor  vn]l  the  edge  be  raised  or  undermined,  and  there  will  be  no  circumferential 
inflammation. 

Connective-tissue  cells  can  proliferate  more  abundantly  in  some  areas  than  in 
others  ;  moreover,  there  are  areas  in  which,  even  if  the  connective-tissue  cells  did 
proliferate  abundantly,  it  would  be  difficult  to  feel  them,  owing  to  the  looseness 
of  the  tissue.  Hence  induration,  when  present,  is  most  marked  when  the  sore  is 
in  the  corona  ;  when  in  the  skin  of  the  penis,  it  seldom  gives  rise  to  more  than  a 
feeling  as  of  parchment,  or  as  if  a  button  were  lodged  in  the  skin.  It  often  happens 
that  sores  on  the  glans  penis  never  become  indurated,  and  the  induration  of  intra- 
urethral  chancres  is,  as  a  rule,  felt  in  one  diameter  only.  There  may  be  almost 
a  circle  of  induration  around  the  corona,  and  yet  be  no  loss  of  surface,  and, 
throughout  the  course  of  the  button-like  nodules  in  the  skin  of  the  penis,  the 
surface  epithelium  may  remain  intact. 

If  there  is  a  sore  on  the  under-surface  of  the  prepuce,  when  the  skin  is  retracted, 
instead  of  the  usual  folds  b^ing  seen,  the  mucous  membrane  is  drawn  out  tightly 
where  the  sore  is,  and  it  rolls  back  as  one  big  piece.  Any  stretching  of  the  part 
where  there  is  induration  formed,  or  forming,  will  produce  a  white  colour,  and  the 
area  left  by  a  recently  healed  sore  is  always  bluish.  As  the  host  cpiickh'  forms 
protective  bodies,  it  will  follow  that,  if  the  sores  are  nmltiple,  the  first  that  appeared 
will  always  be  the  biggest. 

In  some  sores,  the  Leucocijtozoon  st/philidis  develops  aberrantly,  and  does 
not  give  rise  to  sexual  bodies.  As  to  the  percentage  of  such  sores,  I  have  as  yet  no 
knowledge,  but  I  believe  them  to  be  not  very  uncommon.  If  the  asexual  stage  be 
compared  with  the  sexual  stage,  it  will  be  noticed  that  the  development  of  the 
former  is  more  intracellular  than  that  of  the  latter,  and  the  phases  formed  are  less 
motile  ;  therefore,  there  will  be  a  greater  call  upon  the  endothelial  and  connective- 
tissue  cells,  and  the  process  will  be  more  localised.  The  more  the  endothelial  cells 
and  connective-tissue  cells  are  attacked,  the  greater  the  loss  of  nutrition  to  the 
tissue  above,  and  the  greater  the  likelihood  of  early  necrosis.  When  one  set  of 
endothelial  cells  is  finished  with,  the  organisms  will  radiate  peripheral!}',  and  will 
develop  at  the  expense  of  another  set.      Such  a  manoeuvre  will  result  in  the  base  of 

I 


128  THE    BIOLOGY,    CLINICAL   ASPECT    AND    TREATMENT   OF    SYPHILIS. 

the  ulcer  being  uneven,  something  like  a  furrowed  field.  As  the  peripheral  radiation 
may  be  incomplete,  so  far  as  the  whole  circumference  is  concerned,  the  lesion  will 
not  necessarily  be  beautifully  circular,  as  in  the  type  of  chancre  above  described. 
A  spread  of  the  organism  can  more  easily  take  place  when  it  develops  asexually, 
because  the  stimidation  of  the  host's  protective  substances  is  practically  nil.  The 
ulcer  is  extremely  chronic,  not  readily  influenced  by  treatment,  and  the  organisms 
in  the  end  are  most  probably  overcome  by  the  host's  local  protective  mechanism 
only.  This  type  of  sore  is  characterised  by  having  a  raised  edge,  but  it  is  not 
undermined,  and  there  is  no  surrounding  inflammation.  The  reason  why  the 
edge  is  raised  is  perfectly  simple.  Practically  every  chancre,  at  first,  is  a  papule, 
whether  the  organism  develops  sexually  or  asexually ;  since,  in  the  asexual 
development,  the  process  is  more  localised,  the  destruction  of  tissue  will  occur  in 
the  centre  of  the  papule  only,  and  as  the  organism  spreads,  and  the  necrosis  gets 
bigger,  the  protective  cells  will  still  outline  the  infected  area,  and,  where  protective 
cells  are  massed,  there  will  be  a  swelling,  consequently,  the  edge  of  this  type  of 
chancre  is  always  raised.  Moreover,  where  there  is  necrosis,  polymorphonuclear 
leucocytes  congregate,  consequently  a  collection  of  these  will  increase  the  size  of 
the  area  affected. 

In  the  other  type  of  chancre,  in  which  the  nutritive  supply  is  not  wholly  cut 
ofE  in  any  one  sjjot,  but  only  diminished  over  the  whole  area  of  the  infiltration,  it 
will  follow  that  the  erosion  will  correspond  exactly  with  the  infiltrated  area,  hence 
the  edges  will  not  be  raised,  but  the  whole  sore  may  be. 

To  sum  up.  A  primary  sore  is  always  at  first  a  papule,  it  may  remain  so,  but 
it  iisually  becomes  an  erosion.  Induration  then  commences,  ulceration  may  follow, 
and  the  sore  may  become  secondarily  infected.  The  syphilitic  sore  is  sharply 
circumscribed  and  non-inflammatory,  i.e.,  when  compared  \^-ith  inflammation  as 
caused  by  pus-producing  organisms. 

Sometimes  a  primary  sore  may  be  an  ulcer  from  the  start. 

Types  of  Chancres. 

Erosive  chancre. — This  is  the  most  common,  and  it  is  very  frequentlj'  multiple. 
It  is  often  to  be  met  with  on  the  skin  of  the  penis,  and  here  it  might  be  mentioned 
that,  if  a  patient  has  a  sore  or  sores  on  the  skin  of  his  penis,  the  chances  are  90  to  1 
that  they  are  sj'philitic.  The  erosive  chancres  may  encircle  the  corona,  and,  when 
they  occur  on  the  glans  penis,  they  are  the  most  difficult  sores  to  diagnose,  unless 
a  similar  case  has  been  seen  before.  The  erosive  chancres  on  the  glans  penis  are 
multiple,  beautifully  circumscribed,  and  circular,  only  the  most  superficial  part 


Plate  27. — Papulo-erosive  Chancre  in  Corona. 

It  will  be  noticed  that  the  epithelium  has  only  just  been  eroded  in  the 
centre  of  the  lesion  and  that  the  edges  are  white  owing  to  the  fibrous  tissue 
formation,  which  has  produced  induration. 


tracing  p.  128. 


only,  and  a; 


hKosLcO  ra  aiiowAHO  aviaoaa-onjTA^— .TS  ar/^il 

dAi'di  BaBoTO  naad  JBiij  ylno  zbA  muitsdjiqs  9ifj  iedi  booiion  9tl  [tirw  H 
ofteab  euoida  edl  at  gniwo  ojiiv/  9ib  s&gba  orfi  J«rfi  bnc  noiaal  adJ  lo  gnjnao 

.noiJft'iufani  bonnlxnq  and  doidw  ,noi<)«inia) 


^^:^d6'.: 


'  \J 


Plate  27. 


SYPHILIS   OF   THE    SKIN.  129 

of  the  epithelium  is  rubbed  off,  there  is  no  induration,  and,  however  close  the  sores 
may  be  to  one  another,  there  is  no  tendency  to  coalesce. 

The  button  chancre  in  the  skin  of  the  penis  is  an  erosive  chancre,  in  which 
either  the  surface  epithelium  has  never  been  rubbed  ofi,  or  it  has  healed  over  again, 
before  the  patient  seeks  advice. 

The  erosive  chancre  is  the  easiest  chancre  to  diagnose,  and  is  the  one  from 
which  the  Spirochaeta  pallida  is  the  most  easily  obtained. 

In  this  type,  it  is  not  at  all  uncommon  to  meet  with  two  contiguous  chancres, 
i.e.,  one  on  the  under  surface  of  the  prepuce,  and  the  other  on  the  glans  penis,  in 
exactly  corresponding  positions. 

If  the  term  papulo-erosive  chancre  is  applied  to  all  the  types  of  sores  described 
under  the  heading  erosive  chancre,  the  term  papulo-ulcerative  chancre  can  be 
applied  to  those  now  about  to  be  described.  It  is  from  the  papulo-erosive  chancre 
that  the  worst  cases  of  syphilis  arise. 

The  papulo-ulcerative  chancre  may  be  single  or  multiple,  but  the  chief  point 
about  it  is,  that  induration  is  very  frequently  absent.  Under  this  heading  should 
not  be  included  those  erosive  chancres  which  later  become  ulcerative,  because  the 
ulceration  is  purely  secondary  to  the  fibrous  tissue  contraction  ;  in  other  words, 
the  induration  causes  necrosis  by  shutting  off  the  nutritive  supply  from  the  tissue 
above. 

In  the  true  papulo-ulcerative  chancre,  ulceration  occurs  early,  and  is  due  to 
the  organism  itself.  There  is  no  doubt  that  the  Leucocytozoon  syphilidis  develops 
in  a  difierent  way  in  the  papulo-erosive  chancre  to  that  in  which  it  develops  in 
the  papulo-ulcerative  chancre.  In  the  one,  certain  phases  predominate,  in  the 
other,  other  phases.  At  present,  I  am  unable  to  give  more  exact  details  than  this, 
as  I  have  not  examined  a  sufficient  number  of  sores,  from  this  point  of  view. 

Apart  from  the  difference  in  the  development  of  the  organism,  another  very 
important  factor  has  to  be  dealt  with,  and  that  is  the  protective  response  of  the 
host.  In  some  chancres,  a  connective-tissue  celled  hyperplasia,  with  only  a  few 
lymphocytes  and  plasma  cells,  is  the  histological  pictiure  given  ;  while  in  others, 
the  tissue  is  crowded  out  with  plasma  cells.  Whether  the  varied  development 
of  the  organism,  and  the  varied  protective  response  of  the  host,  are  interdependent, 
has  yet  to  be  ascertained,  but  suffice  it  to  say,  at  present,  that  an  exhaustive 
histological  and  bacteriological  study  of  the  various  kinds  of  chancre,  would  throw 
a  considerable  light  upon  the  future  course  of  the  disease  in  each  case,  and  would 
aid  one  in  making  a  prognosis,  and  in  gauging  more  accurately  the  amount  of 
treatment  required.  I  have  been  trying  for  some  time  to  reach  the  same  goal  by 
clinical  means,  i.e.,  to  see  if  there  is  any  connection   between  the  kind  of  sore  and 

i2 


130  THE    BI0L0C4Y,    CLINICAL   ASPECT   AND    TREATMENT   OF    SYPHILIS. 

the  future  course  run  by  the  disease.  Again,  I  have  to  say  that,  up  to  the 
present,  I  have  not  studied  sufficient  cases  for  a  sufficiently  long  period  of  time  to 
be  able  to  make  any  authoritative  statement,  except  in  so  much  that,  generally 
speaking,  the  future  course  is  more  severe  after  papulo-erosive  than  after  papulo- 
ulcerative  chancres.  It  is  not  at  all  uncommon  for  the  papulo-ulcerative  chancre 
to  be  followed  only  by  buccal  lesions  in  the  generalisation  stage.  The  remark 
made  about  the  severity  of  the  case  is  also  borne  out  by  my  histological  and 
bacteriological  examinations  of  chancres  and  lymphatic  glands  removed  from  the 
set  draining  the  primary  sore.  Many  more  organisms  are  found  in  the  papulo- 
erosive  than  in  the  papulo-ulcerative  chancre,  and  many  more  organisms  are 
found  in  the  small  and  hard  lymphatic  glands  than  in  the  swollen  and  soft  ones. 
As  regards  the  host's  protective  response,  the  state  of  affairs  is  exactly  reversed — 
that  is  to  say,  in  the  papulo-ulcerative  chancre,  and  in  the  large  lymphatic  gland, 
the  greatest  numbers  of  lymphocytes  and  plasma  cells  are  to  be  met  with.  In 
the  erosive  chancre,  and  in  the  small  and  hard  lymphatic  gland,  connective-tissue 
cells  and  endothelial  cells  predominate. 

Of  the  papulo-ulcerative  chancre  there  are  several  kinds.  Each  kind  may 
receive  a  different  name,  but  it  must  be  understood  that  many  are  onl\-  different 
stages  of  the  same  sore,  and  they  vary,  according  to  tiie  degree  of  the 
ulceration. 

Simple  papulo-ulcerative  chancre. — This  chancre  is  often  very  small,  it  is 
frecpiently  missed,  and  in  many  of  the  so-called  cases  of  Syphilis  (Temblee — i.e., 
in  which  no  primary  sore  could  be  found,  there  was  one  present  of  this  nature. 

In  the  larger  sores,  the  ulceration  ma}"^  or  may  not  be  covered  with  a  crust. 
The  crust  must  always  be  removed,  before  a  diagnosis  is  made.  In  an  ulcer  which 
has  a  crust,  the  base  is  covered  with  pus,  and  the  margin  of  the  ulcer  is  red  and 
inflamed,  owing  to  the  proteolytic  action  of  the  crust.  If  the  crust  is  removed,  as 
a  rule  it  will  be  found  to  cover  the  whole  area  of  the  sore,  not  only  the  centre^'as  is 
the  case  in  an  ulcer  of  pyogenic  origin.  The  base  is  smooth,  the  edges  are  not  raised, 
they  are  never  undermined,  and,  in  most  cases,  the  circumference  is  perfectly  regular. 

This  type  of  chancre  may  occur  anywhere  on  the  penis,  but  it  is  commonly 
to  be  found  on  the  froemim,  or  on  the  corona,  just  by  the  froenum.  Occasionally 
there  are  two  sores  on  the  corona,  one  on  either  side  of  the  froenum,  and  they  may 
coalesce  and  ulcerate  through  the  froenum. 

Ecthymatous  chancre. — This  chancre  is  most  frequently  found  on  the  skin. 
It  is  usually  single,  sharph'  circumscribed,  raised,  and  crusted  on  the  surface. 
Considering  the  appearance  of  the  sore,  the  amount  of  surrounding  inflammation 
is  less  than  might  be  expected. 


Plate  2S. — Papulo-erosive  ('hancre  on  Tm5  Under  Surface  op  the 

Prepfck. 

It  will  be  noticed  that  the  prepuce  has  been  withdravm,  bringing  into  view 
a  white  or  swollen  area,  over  which  the  folds  of  the  prepuce  are  absent.  The 
lesion  felt  like  a  button,  there  had  never  been  any  loss  of  surface  and  the 
appearance  is  white,  owing  to  the  fibrous  tissue  constricting  the  blood  vessels, 
when  put  on  the  stretch. 


FacinQ  p.  130. 


aHT  ia  ao*."»aay  smcmU  awT,  ho  aaoHAsO  av:ip.oaa-ounMA9m.ftS  awa'^  ,.i 

n-t\i  (M>ii  yiii^iiri.l  ,11 /(hi[iilJi»(  11-vin  <iA\  vyi/qsncf 'ect.f'^ifiHt  b'Kjijort" 3fl  ffHiJ-'il  ■'' 
9riT  .tnsBdj;  ai*  sacq^q  sill  io  sbfo^  ertJ  rfoiriv/  i9vo  ,BeT«  nallowg  10  aiiit-B  « 
arit  bdis  "ioeiTug  I0  eaol  vnjs  (\')'^(\  laygii  f)Bd  aisfll  .ticttod  «  ajlil  ifVt  nojeel 
.nl'iw)-/  IkjoK!  *)f(t  <^iiit'ih)K(ifii  'p|)«?.fj  sijoKfil  oil)  ot  gniwo  ,iiiri7;  ai  aonBiBaqqr. 

.rfot^ia  adl  no  *uq  nad-w 


.osr  .<(  ^hn'^ 


u 


yjf' 


?.#■ 


Plate  28. 


SYPHILIS   OF   THE    SKIN.  131 

Phagedaenic  chancre. — This  is  only  a  further  stage  oi  t!ie  preceding,  in  which 
a  secondary  iniection  has  supervened.  The  secondary  infection  is  usually  due  to 
the  symbiotic  Gram  negative  spirochaeta  and  Gram  positive  fusiform  bacillus. 

Pseudo-membranous  chancre. — These  chancres  are  usually  multiple  ;  they  are 
about  the  size  of  a  threepenny  piece,  and  always  sharply  circumscribed  ;  the 
surface  may  be  flush  with  the  surrounding  skin,  or  even  raised  above  it ;  the  base 
is  yellow  ;  nothing  can  be  rubbed  of?  ;  it  is  surrounded  by  a  sharply  circumscribed 
red  ring  ;  and  the  sore  is  generally  slightly  indurated.  A  favourite  localisation 
is  on  the  under  surface  of  the  prepuce,  and,  when  the  prepuce  is  withdrawn,  the 
folds  are  missed  in  the  areas  where  the  sores  are  situated. 

Hypertrophic  chancre. — This  chancre  is  almost  invariably  single,  and  is  most 
frequently  met  with  on  the  pubis.  It  presents  no  difficulty  in  diagnosis.  A 
chancre  in  this  region  is  sometimes  an  ulcerative  one,  usually  of  fairly  large 
dimensions,  and  frequently  sores  are  to  be  met  with  which  combine  the  two  types. 

Regarding  a  chancre  from  the  point  of  \\e\y  of  its  site,  will  allow  of  the  mention 
of  several  little  diagnostic  points. 

Intraurethral  cJiancre. — I  have  yet  to  see  in  the  urethra  a  primary  sore  which 
is  wholly  urethral,  and  which  cannot  be  seen  with  the  naked  eye.  In  every  case 
I  have  seen,  and  the  urethra  is  not  at  all  an  uncommon  site,  one  pole  of  the  sore 
has  always  involved  the  glans  penis.  The  sore  quickly  causes  a  narrowing  of  the 
orifice,  and  it  gives  rise  to  an  induration  which  is  best  felt  by  pressing  the  glans 
between  the  forefinger  and  thumb,  from  above  downwards.  "When  palpated  from 
side  to  side,  the  induration  is  frequently  missed.  If  the  patient  has  a  tight 
foreskin,  and  the  orifice  of  the  urethra  cannot  be  seen,  the  chances  are  that  the 
phimosis  has  been  largely  produced  by  the  syphilitic  lymphangitis,  in  which  case 
the  glans  penis  feels  hard  all  over. 

Lymphadenitis  is,  as  a  rule,  an  early  sign,  and  the  patient  enters  the  generalisa- 
tion stage  quickly.  I  have  seen  many  urethral  sores  in  which  the  patient  ran  a 
sharp  evening  temperature,  probably  owing  to  the  fact  that  the  urethra  is  lined 
by  a  mucous  membrane  through  which  the  organisms  can  easily  gain  access  into 
the  circulation,  and  so  set  up,  before  the  patient  can  protect  himself,  a  widespread 
generalised  infection. 

Primary  sore  in  corona,  uifh  phimosis. — These  cases  can  usually  be  diagnosed 
at  the  first  glance.  The  prepuce  is  swollen  on  the  side  on  which  the  sore  is  situated, 
and  the  swelling  is  non-inflammatory.  When  it  is  palpated,  the  induration  is  at 
once  ob\aous.  Sores  which  are  complicated  by  phimosis,  are  usually  of  the  papulo- 
erosive  type,  in  which  induration  is  a  prominent  feature,  and  the  phimosis  is  often 
produced  by  the  widespread   indurative  syphilitic  infiltration  of  the  lymphatics. 


132  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

and,  possibly,  of  the  smaller  veins  and  arterioles.  This  syphilitic  infiltration 
imparts  a  blue  to  violet  colouration  to  the  part,  and  this  is  so  pathognomonic  of 
syphilis  that,  once  seen,  it  will  never  be  forgotten. 

Extragenital  Chancres. 

Extragenital  chancres  may  occur  anywhere,  and  they  are  generally  very  easy 
to  diagnose.  The  sore  is  nearly  always  single,  but  occasionally  erosive  chancres 
of  the  amis  and  lips  are  multiple,  in  which  case  the  sores  are  contiguous.  The 
sores  have,  as  a  rule,  been  present  for  some  time  before  the  patient  seeks  advice  ; 
hence  an  enlargement  of  the  lymphatic  glands  draining  the  infected  site  is  prac- 
tically never  missed.  However  big  the  sore  may  be,  and  many  of  the  extragenital 
chancres  are  of  the  ulcerative  and  hypertrophic  t}^e,  the  amount  of  siurounding 
inflammation  is  always  minimal,  and  this  at  once  excludes  a  pyogenic  lesion. 

If  the  sore  is  on  a  mucous  membrane,  as  all  intrabuccal  sores  are,  the  glandular 
enlargement  is  always  very  pronounced,  and,  however  closely  a  sore  on  the  tonsil, 
for  instance,  may  simulate  or  suggest  a  chancre,  syphilis  can  be  at  once  excluded, 
if  the  lymphatic  glands  are  not  enlarged  in  the  submaxillary  regions,  and  in  all 
the  triangles  of  the  neck.  In  the  case  of  a  pyogenic  infection,  and  in  Vincent's 
angina,  the  enlargement  of  the  lymphatic  glands  is  negligible,  compared  with  a 
syphilitic  enlargement,  and,  moreover,  they  are  only  enlarged  in  the  submaxillary 
region  on  the  side  affected. 

A  common  extragenital  chancre  is  the  digital,  and,  as  a  rule,  it  is  situated  in 
the  margin  between  the  nail  and  the  skin.  There  is  nearly  always  a  swelling  of  the 
epitrochlear  gland,  which  not  infrequently  goes  on  to  suppuration.  Suppiuration 
in  the  region  of  the  inner  side  of  elbow  should  always  raise  the  suspicion  of  a  digital 
chancre,  as  I  have  seen  three  cases  operated  upon  for  supposed  cellulitis,  when 
the  real  nature  of  the  disease  was  missed. 

It  should  not  be  forgotten  that,  in  cases  of  anal  infection,  the  lymphatic  gknds 
to  be  enlarged  are  the  inguinal.  It  is  important  to  remember  this,  as  the  diagnosis 
of  Syphilis  d'embhJe  has  been  made  when  no  sore  on  the  genitals  could  be  found. 

Syphilis  d'Emhlee. 

Syphilis  d'emblee  is  the  term  applied  to  cases  of  acquired  syphilis,  in  which 
no  primary  lesion  exists.  The  possibility  of  this  is  often  questioned — possible  it 
certainly  is,  and  cases  are  from  time  to  time  met  with,  but  the  condition  is  often 
hard  to  prove,  as  some  syphilitic  sores  are  so  small,  and  others  heal  quickly  without 
leaving  any  mark  behind  them.     I  have  had  two  cases  of  Syphilis   cVemblee,  in 


Plate  29. — A  Chancre  of  ttte  Froenttm. 


It  will  be  noticed  that  the  sore  is  slightly  ulcerated  and  covered  with  pus. 
The  acre  is  really  a  papulo-erosive  chancre,  in  which  slight  ulceration  has 
occurred,  probably  owing  to  the  fact  that  the  foreskin  was  tight,  and  therefore 
the  conditions  in  the  region  of  the  sore  were  practically  anaerobic.  The 
most  characteristic  point  and  the  most  important  diagnostic  sign  is  the 
non-inflammatory  oedema  of  the  prepuce,  produced  liy  the  left  half  of  the 


Pi.ATi': 


Pacing  p.  132. 


g  the  S'  any  of  the  < 

amount  of  ^^: 


.'  .#ifV*oitT  smr  irJ'BgoVTASS  A^— .89  stajH 


:(:]mI, 


.sij(7  ffiJT/  fjmsvoo  firrr,  FiHtrn-poftr  v'trigila  si  9no8  arfi  ijsrfl  baoiiori  ed  Uiw  11 

adT;  .oidoiaBfiiB  Y.IffioiioB'Kl  sisw  s'lOB  sdJ  Jo  noigwi  srfl  "i  f.noilibooo  ad* 
9rit  81  n§i«  oitsoti^ib  iuiiJioqiui  iaora  oilJ  bne  laioq  oUansJ^BiB^ia  isoto 
^(iD  1o  >[r(I  tt'il    xh  -/.I  fifiif(i(n)|  .'VKFccvKi    irll  1o  isni')F)>fi  vKili'.niiii/iRrij-nori 

.9108 


uuaus. 


■ '.SSl  !<  <!»V4l)'t 


Plate.  29. 


SYPHILIS   OF   THE    SKIN.  133 

which  the  infection  -was  a  direct  one  into  the  blood  stream.  The  first  sign  and 
symptom  was  the  rash,  and  neither  patient  had  any  enlargement  of  his  lymphatic 
glands.  One  of  the  patients  was  a  medical  man,  and  the  other  a  medical  student, 
and  both  were  looking  after  syphilitic  cases  when  the  rash  appeared.  The  medical 
man  remembered  pricking  his  finger,  while  giving  a  mercurial  injection,  but  no 
sore  developed  at  the  site. 

Differential  Diagnosis. 

A  chancre  may  be  confounded  with  a  traumatic  lesion,  soft  sore,  Herpes 
genitalis,  aphthous  ulcer,  and  Balanitis  erosiva  et  gangrenosa. 

A  traumatic  lesion  is  irregular  in  outline,  it  is  an  ulcer  in  parts,  and  an  erosion 
in  parts,  at  one  pole  it  often  is  difficult  to  say  where  the  trauma  ends  and  the 
healthy  skin  begins,  the  lesion  soon  becomes  infected  with  pyogenic  cocci,  hence  it 
is  surrounded  by  an  area  of  inflammation  ;  unless  soon  healed,  pseudo-induration 
may  occur,  and  the  sore  is  usually  situated  on  the  froenum. 

Soft  sore. — The  incubation  period  of  a  soft  sore  is  a  few  days.  It  is  an  ulcer 
almost  from  the  start,  at  first  cpite  superficial,  and,  later,  deep.  The  circumference 
is  irregular,  although  sharply  circumscribed,  because  one  pole  of  the  ulcer  tends 
to  heal,  while  the  other  pole  is  spreading.  Most  ulcers  have  a  zone  of  protective 
cells  surrounding  them,  which  causes  the  edge  to  be  raised.  If  the  cause  of  the  ulcer 
is  an  organism  which  produces  pus,  and  nearly  all  organisms  which  do  form  pus 
spread  very  quickly  in  the  superficial  part  of  the  lesion,  as  they  prefer  aerobic 
conditions,  it  will  be  readily  understood  how  easily  the  raised  edge  can  be  under- 
mined. Ducrey's  bacillus,  the  organism  which  causes  the  soft  sore,  fulfils  all  these 
conditions,  and,  as  it  is  a  pus-producing  organism,  every  lesion  is  surrounded  by 
an  area  of  inflammation,  which  is  naturally  most  pronounced  at  the  spreading  part 
of  the  ulcer,  where  the  edge  is  also  most  undermined. 

Some  soft  sores  are  very  chronic,  and  they  may  become  pseudo-indurated, 
but  they  nevertheless  still  retain  the  characteristics  above  mentioned. 

If  a  primary  sore  is  about  to  develop  on  a  soft  sore,  i.e.,  if  the  patient  has  a  mixed 
infection,  an  occurrence  frequently  met  with  in  text  books,  but  not  in  practice, 
the  base  of  the  ulcer— not  as  a  rule  the  whole  of  it  at  one  time — becomes  raised, 
the  distinct  raised  and  undermined  edge  vanishes,  the  ulcer  looks  more  like  an 
erosion,  and  the  loss  of  surface  is  often  raised  above  the  level  of  the  surrounding 
skin,  or  is  flush  with  it.  Induration  is  a  late  phenomenon,  and  only  becomes 
manifest  when  the  chancre  begins  to  heal. 

Herpes  genitalis  is  primarily  a  vesicular  eruption  of  nervous  origin,  and  is  very 
apt  to  recur.  The  lesions  are  grouped.  They  may  quickly  become  crateriform 
ulcers,  and,  if  treated  with  caustics,  pseudo-induration  is  certain  to  supervene. 


134  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMKXT   OF   SYPHILIS. 

As  a  rule,  herpes  is  onl_y  confounded  with  syphilis,  when,  under  energetic  treatment, 
the  lesions  get  worse  instead  of  better.  Herpes  is  primarily  a  lesion  due  to  irritation, 
therefore  it  follows  that,  the  longer  the  irritation  is  kept  up,  the  more  chronic  the 
lesions  will  become. 

An  aphthous  ulcer  is  also  due  to  irritation,  and  is  likewise  of  nervous  origin. 
It  occurs  quickly,  and,  before  the  patient  is  aware  that  anything  is  wrong,  a 
characteristic  ulcer  or  ulcers,  as  they  are  frequently  multiple,  have  developed. 

The  lesion  is  small,  sharply  circumscribed,  generally  circular,  the  base  of  the 
ulcer  is  smooth,  yellow  and  depressed,  the  edge  is  not  raised,  but  is  marked  by  a 
narrow  red  inflammatory  ring,  which  is  sharply  cut  off  from  the  healthy  skin  just 
external  to  it. 

Balanitis  erosiva  et  gangrenosa  is  a  condition  which  consists  of  several  lesions, 
which  spread  extremely  rapidly,  and  cause  more  destruction  in  twenty-four  hours 
than  a  syphilitic  lesion  would  do  in  a  month.  The  incubation  period  is  short,  the 
organisms  causing  the  trouble  will  only  develop  under  anaerobic  conditions, 
therefore  the  lesions  will  begin  to  heal  in  a  few  hours,  if  left  exposed  to  the  air  and 
frequently  bathed  with  hydrogen  peroxide. 

Skin  Eruptions  of  the  Generalisation  Stage. 

It  has  been  cu.stomary  to  divide  the  cour.se  of  .syphilis  iuto  three  stages,  i.e., 
primary,  secondary,  and  tertiary. 

The  primary  stage  only  included  the  chancre. 

The  secondary  stage  began  when  the  headaches  appeared,  and  when  the  patient 
developed  a  rash  and  sore  throat. 

The  tertiary  stage  began  after  the  second  year. 

Symptoms  of  the  secondary  stage  may  be  met  with,  years  after  the  infection. 
There  is  a  common  opinion  that  secondary  syphilis  is  unimportant,  compared  with 
tertiary  syphilis.  From  these  facts,  it  seems  to  me  to  be  wiser  to  abandoix  the 
above  nomenclature,  and  to  adopt  the  following  : — 

The  stage  of  the  initial  lesion,  i.e.,  the  chancre. 

The  stage  of  the  generalisation  of  the  virus.  All  symptoms  arising  while  the 
organisms  are  pervading  every  nook  and  crevice  in  the  body  would  be  included  in 
this  stage.  The  latent  stage,  i.e.,  the  period  during  which  the  patient  has  no 
symptoms,  or,  in  other  words,  the  period  during  which  the  organisms  are  dormant. 

The  recurrent  stage,  or  "the  stage  in  which  symptoms  recur  after  the  ^^rus 
has  become  generalised.      Gummata  may  be  considered  as  a  variety  of  this  stage. 

For  the  moment,  we  are  concerned  with  the  stage  of  the  generalisation  of  the 
virus. 


Plate  30. — A   Chancre  in  One  of   the  Furrows  op   the  Preptjck. 

It  will  be  noticed  that  only  one  furrow  is  ulcerated,  that  the  sore  is  sharply 
(■ircumscribed,  red  on  the  surface  and  not  surrounded  by  inflammation. 
When  a  primajy  sore  occurs  on  the  tip  of  the  prepuce  it  nearly  always  produces 
a  non-inflammatory  oedema  of  the  whole  of  the  prepuce  ;  a  point  which  is 
well  brought  out  in  the  painting. 

If  the  sore  had  been  a  soft  sore,  it  is  tolerably  certain  that  there  would 
have  been  a  sore  in  every  furrow,  and  that  a  condition  of  phimosis  would 
have  been  produced  owing  to  the  acute  inflammatory  oedema  of  the  foreskin, 
which  always  accom])anie.s  a  pyogenic  infection. 


Facing  p.   134 


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aoi^aatai  srnsgoAnf  «  asi/tttimoaotr  ^«{.B«l(li|{o|dw 


fluded  ii 


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Plate  30. 


Plate  31. — A  Papxjlo-plcerative  Chancre  on  the  Upper  Sukface  of  tht! 

Prefuoe. 

It  will  be  noticed  that  the  sore  is  sharply  circumscribed  and  regular  in 
outline,  that  there  is  a  moderate  loss  of  surface,  that  the  base  of  the  ulcer  is 
not  covered  with  pus  and  that  the  edges  are  raised,  slightly  everted,  but 
not  undermined.  There  is  no  surrounding  inflammation,  but  only  a  non- 
inflammatory oedema  of  the  foreskin.     The  sore  was  not  indurated. 

From  this  type  of  sore  many  spiroohaetae  may  be  obtained.  Extra- 
cellular forms  are  also  to  be  found.  The  histology  of  it  is  quite  different 
from  that  of  the  papvdo-erosive  chancre.  The  cellular  infiltration  is  much 
more  marked  and  instead  of  consisting  mainly  of  connective-tissue  cells 
and  plasma  cells,  it  is  made  up  mostly  of  lymphocytes  and  poljanorpho- 
nuelear  leucoojrtes.  The  connective-tissue  cells  are  increased,  especially  those 
in  the  walls  of  the  blood  vessels,  but  they  are  hypertrophied,  somewhat 
degenerated,  non-pyroninophile  and  therefore  they  do  not  develop  into 
fibrous  tissue.  There  is  a  slight  hyperplasia  of  the  endothelial  cells. 
The,  what  may  be  called  oedematous  condition  of  the  walls  of  the  blood 
vessels  is  characteristic  of  this  kind  of  sore.  The  phases  of  the  Leucocytozoon 
syphilidis  are  very  sparse  and  have  lost  their  usual  pjToninophile  properties. 

The  lymphatic  gland  enlargement  which  accompanies  this  type  of  sore 
is  as  a  rule  very  pronounced,  but  the  lymphatic  glands  are  not  hard,  like 
those  which  accompany  the  papulo-erosive  sore.  However,  in  the  latter  case 
the  glands  are  often  not  enlarged,  and  always  remain  discrete. 

This  type  of  sore  is  an  indication  of  the  host's  high  protective  power 
against  the  infection,  hence  the  disease  usually  runs  a  mild  course.  Very 
often  no  signs  of  the  generalisation  of  the  virus  appear. 


Follows  Plate  30, 


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.aijijiaa*! 

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.laaqqa  ainiy  adi  io  uoitaeilaienag  adl  io  angia  on  naJlo 


,08  »hiS1  mioWo'l 


Plate  31. 


SYPHILIS    OF   THE    SKIN.  135 

Tlie  organisms  reach  the  skin  by  the  blood  stream,  and  they  begin  to  develop 
in  the  uppermost  la}^ers  of  the  corium.  The  macule  is  the  first  indication  of  the 
local  development  of  the  parasites,  the  roseola  being,  in  my  opinion,  the  first 
indication  that  the  organisms  have  reached  the  skin,  and  it  is  of  the  nature  of  a 
toxic  ra.sh.  When  the  organisms  firi5t  reach  the  skin,  they  act  as  foreign  bodies. 
The  host  will  make  an  attempt  at  defence,  which  is  signalled  by  a  dilatation  of  the 
capillaries.  This  dilatation  allows  more  blood  to  come  to  the  skin,  with  the  result 
that  it  gets  redder,  the  so-called  roseola. 

Later,  owing  to  the  fact  that  the  organisms  are  developing  in  areas,  and  not 
equally  all  over  the  skin,  the  generalised  roseola  gives  place  to  the  more  localised 
macule. 

The  macule  varies  in  size,  from  that  of  a  threepenny  piece  to  that  of  a  half- 
crown.  Although  more  or  less  circular  in  outline,  its  circumference  cannot  be 
accurately  mapped  out,  as  it  is  difficult  to  say  where  the  macule  ends  and  where  the 
healthy  skin  begins.  This  is  due  to  the  fact  that  the  macule  does  not  accurately 
correspond  with  the  area  in  which  the  organisms  are  developing.  The  macule  is 
mainly  a  toxic  phenomenon,  like  the  roseola.  Later,  in  the  centre  of  a  macule, 
a  papule  appears,  and,  from  this  time  onwards,  the  macule  gradually  fades,  and 
finally  vanishes.  The  papule  slowly  increa.ses  in  size,  but  scarcely  ever  covers  the 
entire  area  of  the  macule. 


O 


PAPULE    DEVELOPING    IN 
CEXTF.E    OF    MACULE. 


In  some  of  the  larger  macules,  a  tiny  little  papule  appears  in  the  region  of  each 
hair  follicle. 


FOLLICULAR   SYPHILIDE. 


Occasionally  it  happens  in  the  follicular  syphilide  that  the  central  papule 
develops  in  the  ordinary  way.     This  lesion  receives  the  name  of  corymbose  s}'philide. 


CORYMBOSE    SYPHILIDE. 


136  THE    BI0L0C4Y,    CLINICAL   ASPECT  AND   TREATMENT   OF   SYPHILIS. 

As  a  rule,  the  follicular  and  corymbose  syphilides  are  most  marked  on  the 
back,  especially  along  a  transverse  line  drawn  through  the  centre  of  both 
scapulae. 

When  a  papule  begins  to  disappear,  it  develops  scales,  and,  as  the  central  part 
of  a  papule  is  the  oldest  part,  retrogression  will  commence  in  the  centre,  in  the 
same  way  as  the  papule  develops  in  the  centre  of  a  macide.  The  result  is,  that  the 
scales  will  be  found  only  in  the  middle  of  the  papule.  When  the  whole  papule  has 
begun  to  retrogress,  naturally  its  whole  area  will  be  covered  with  scales,  but  there 
are  bound  to  be  some  papules  elsewhere  on  the  bodj',  and  in  them  only  the  central 
part  has  scales. 

Owing  to  this  unequal  development,  a  macule  may  exist  near  a  scaly  papule, 
and  it  is  this  polymorphic  character  of  the  first  syphilitic  rash  which  is  so  diagnostic. 
The  polymorphism  is,  I  think,  another  point  in  favour  of  my  life-cycle  view,  because 
it  would  be  difficult  to  explain  why  lesions  in  various  stages  should  be  met  with 
when  the  spirochaetae  are  evenly  distributed  over  the  skin  at  the  same  time.  The 
explanation  is  smiple  on  the  basis  of  my  life-cycle  \-iew,  because  so  many  phases 
have  to  be  perfected  before  the  end  phases  are  in  sufiicient  number  to  give  rise  to 
symptoms  ;  and,  in  the  process  of  formation  of  these  phases,  so  many  factors  may 
arise  to  hinder  their  development.  A  papule  need  not  necessarily  become  scaly, 
it  may  degenerate  in  the  centre  instead,  with  the  result  that  a  pustule  forms.  Some 
of  these  pustular  lesions  are  not  unhke  varicella,  but  the  distinction  between  the  two 
becomes  simple,  when  the  anatomy  of  the  two  lesions  is  considered. 

In  varicella,  the  organism  develops  in  the  epithelial  cells.  These  cells  de- 
generate, and,  owing  to  the  presence  of  the  lymph  between  them,  a  vesicle  is  formed. 
As  the  degeneration  extends  to  the  corium,  and  leucocytes  can  obtain  entrance  to 
the  vesicle,  it  is  quickly  turned  into  a  pustule. 

As  the  organism  develops  in  the  epithelium,  the  surrounding  toxic  or  area! 
inflammation  will  be  minimal,  with  the  result  that,  when  the  vesicle  is  first  formed, 
it  will  cover  practically  the  whole  lesion.  Since  the  vesicle  forms  in  the  epithelium, 
it  follows  that  the  roof  is  very  thin  and  insecure.  The  syphilitic  organism,  on  the 
other  hand,  develops  in  the  corium.  Degeneration  of  the  corium  leads  to  a  pustule 
at  once,  therefore  no  vesicular  lesions  will  be  found.  The  degeneration  occurs 
primarily  in  the  centre  only,  therefore  the  pustule  will  not  cover  the  whole  area 
taken  up  by  the  papular  lesion.  The  degeneration  commences  in  the  corium, 
therefore  the  roof  of  the  pustule  will  not  be  thin  and  insecure. 

The  whole  papule  may  degenerate,  and  then  usually  a  crust  forms.  Owing 
to  the  strong  proteolytic  action  of  crusts,  degeneration  of  the  subjacent  tissue  may 
continue.     The  underlj'ing  tissue  may  be  digested  in  the  centre  only,  or  at  the 


SYPHILIS    OF   THE    SKIN.  137 

periphery.  If  the  former,  there  will  be  a  heaping  up  of  the  crust  in  the  centre, 
so  that  ultimately  it  will  resemble  a  limpet  shell. 

If  the  latter,  the  lesion  will  increase  in  circumference,  but  not  in  depth. 

To  either  or  both,  the  term  rupial  syphilide  is  frequently  given. 

Another  very  typical  early  skin  eruption  is  the  so-called  seborrhoeic  syphilide. 

The  lesions  may  be  the  first  to  appear,  and,  on  the  whole,  they  are  commoner 
in  women  than  in  men.  They  are  circular,  the  edge  is  often  rai.sed,  the  centre  is 
yellowish,  and  the  whole  lesion  looks  as  if  it  were  covered  with  very  fine  fatty  scales, 
which  come  more  into  evidence  when  the  lesion  is  rubbed. 

The  lesions  invariably  occur  on  the  face,  and  some  are  always  situated  at  the 
corners  of  the  nose  and  mouth.  A  papule  in  a  moist  area  may  become  oedematous 
and  hypertrophic,  and  then  it  receives  the  name  of  Condyloma  latum.  Cotidy- 
lomata  lata  are  most  usually  seen  about  the  genitals  and  the  anus,  but  they  may 
also  occur  in  the  rmibilicus,  axillae,  eyelids,  and  between  the  toes.  A  papulo- 
pustular  lesion  may  become  oedematous  and  hypertrophic,  when  it  receives  the 
name  of  framboesiform  syphilide.  The  scalp  is  the  most  commonly  affected  part, 
but  I  have  seen  them  on  the  palms  of  the  hands. 

The  syphilitic  alopecia  is  the  result  of  a  maculo-papular  eruption  of  the  scalp, 
and  occurs  in  the  following  way.  Where  the  true  macule  occurs,  there  is  little  or  no 
loss  of  hair.  Where  the  true  papule  occurs,  there  is  complete  loss  of  hair,  and,  in 
the  area  between  the  two,  the  loss  of  hair  is  less.  This  accounts  for  the  irregularity 
of  the  loss  of  hair  which  is  characteristic  of  syphilitic  alopecia. 


\  -MACDLO-PAPTJLE. 

;'  '  ' 


MACULE. 


Typical  alopecia  areata  may  occur  in  early  syphilis,  but  this  is  an  atrophic 
phenomenon.  A  similar  atrophic  condition  may  affect  the  nails.  Another  charac- 
teristic lesion,  for  which  both  the  macule  and  the  papule  are  responsible,  is  the  so- 
called  Leucoderma  syphiliticum. 

The  lesions  may  appear  singly,  or  in  rosettes.  They  are  roughly  circular  in 
outline,  about  the  size  of  a  sixpenny  piece,  and  are  depigmented. 

Occasionally,  in  the  depigmented  areas,  a  hyperpigmented  spot  may  be  observed. 
The  former  corresponds  to  the  macule,  and  the  latter  to  the  papule. 

Leucoderma  syphiliticum  is  most  common  in  women,  because  the  skin  is  more 


138  THE    BIOLOGY,    CLINICAL    ASPECT   AND    TREATMENT   OF    SYPHILIS. 

delicate,  aud  therefore  the  lesion  can  be  more  easily  seen.  For  the  same  rea.son  it 
is  more  apparent  in  brunettes  than  in  blondes. 

It  is  most  frecjuently  seen  on  the  neck  and  the  folds  of  the  axillae,  but  it  may 
affect  practically  the  whole  trunk.  It  disappears  in  course  of  time,  but  is  un- 
influenced by  treatment.  Naturally,  the  clinical  appearances  of  papules  will  vary 
according  to  their  localisation.  The  so-called  mucous  patches  are  papules  occurring 
in  mucous  membranes.  Striking  lesions  of  the  nails  may  occur,  according  to  the 
position  of  the  papule,  and  the  manner  in  which  it  develops. 

A  papule  may  occur  far  back  at  the  base,  and  injure  the  bed  of  the  nail,  with 
the  result  that  the  development  of  the  nail  is  impaired.  A  characteristic  doughy 
feeling  of  the  base  ensues,  and  the  nail  is  atrophied  and  soft. 

A  papule  may  break  through  the  centre  of  the  nail,  or  develop  at  the  sides, 
and,  provided  that  it  remains  dry,  it  not  infrequently  causes  a  brown  to  black  dis- 
colouration of  the  nail. 

All  the  lesions  so  far  described  are  discrete,  but  there  is  a  diffuse  syphilitic 
lesion  to  which  sufficient  attention  has  not  been  drawn,  but  nevertheless  it  is  very 
characteristic  of  the  disease.  This  lesion  is  a  diffuse  papular  infiltration  of  the 
skin  of  the  penis,  and  it  arises  bj^  a  direct  spread  of  the  organisms  from  the  chancre 
(Plate  32).  This  lesion  is  not  an  uncommon  one,  and  it  may  well  have  retro- 
gressed before  the  generalised  eruption  puts  in  its  first  appearance.  It  is  not  at 
all  uncommon  for  the  first  and  the  most  developed  lesions  to  appear  in  the  neigh- 
bourhood of  the  primary  sore.  Occasionally,  the  maculo-papules  on  the  trunk 
may  lead  to  true  atrophy  of  the  skin.  The  atrophic  lesion  corresponds  with  the  area 
covered  by  the  maculo-papulc.  The  skin  is  wrinkled  ;  it  looks  as  if  it  were  raised  ; 
it  feels  very  soft  and  thin  ;  and  a  pit  is  generally  to  be  ascertained  on  pressure. 
Atrophic  lesions  are  most  frequently  met  with  on  the  shoulders,  especially  over 
the  scapulae  behind.     Naturally,  the  lesions  never  alter. 

Recurrent  Suphilific  ErujAions.  ^ 

All  recurrent  syphilides  tend  to  appear  in  circles  or  in  segments  of  circles,  owing 
to  the  peripheral  spread  of  the  organisms  from  the  region  in  which  they  were,  when 
their  development  gave  rise  to  the  papule.  The  lesion  may  appear  as  a  single  circle, 
the  so-called  orbicular  syphilide,  or  concentric  circles  may  appear,  the  so-called 
annular  syphilide. 


ORBICULAR    SYPHILIDE.  ANNULAR    SYPHILIDE. 


Plate  32. 

This^Ts^  paintrng  to  snow  the  diffuse  papular  eruption  on  the  genitals 
which  arises  by  a  direct  extension  of  the  organisms  from  the  primary  soro. 
In  this  case  the  primary  sore  is  intrauiethral.  The  patient  had  no  other 
signs  of  syphilis,  and  it  is  usual  for  this  rash,  localised  to  the  genitals,  to  appear 
several  weeks  before  the  generalised  rash  manifests  itself. 


Facing  p.  138. 


'wn  to  black  dLs- 


' '  noitquia  tasJuqccf  ■jsu;'flib  srlJi  y/oda  oi,  gi:(U(ii«q  >;  ai  airiX       ,  , 
■  1.1'.  7;ii;uiiiq  'jilt   mcil  a/tiairiBg-io  ari,}  to  noianoJza  Joaiib  b  y.c'  asai'ifi  rioiri// 
isrfito  ofiburi   tnoitBq  oHT      .(r/rrftnrrinjrii  ai  9'io?.  yiiunhq  odJ  9suo  nixll  til 
njisqqfi  o*  ,al*Ji(i9§  ariJ  oJ  baeitKOoI  ,de«T  Mi  tol  FjSobii  «i  .)i  bnjs  ,8i[i(lqY,8  lo  angie  ^' 

3    on    tbr    tTU;;k 

osponds  "■- 


^Vn^' 


.881  .i\  ^itno'^ 


ifVX, 


""***  _  -,>'   ^f^^^ 


Plate  32. 


SYPHILIS    OF   THE    SKIN.  139 

The  commonest  recuiTent  lesions  are  not  so  regular  as  the  two  just  mentioned  ; 
either  the  whole  circle  is  made  up  of  distinct  papules  or  only  a  segment  of  it  is 
apparent. 


0                   g 

0 

% 

Not  infrequently,  the  original  papule  itself  recurs, 

as,  often  in  the  middle  of  the 

circular  lesions  a  papule  is  seen. 

0     © 

0 

It  can  be  easily  understood  that,  as  the  papules  in  the  circumference  of  the 
circle  mark  the  limit  of  extension  of  the  organisms  from  the  centre,  some  of  the 
organisms  may  have  remained  half  way,  for  instance.  This  will  result  in  papules 
being  found  in  the  recurrent  lesion  along  any  part  of  any  radius  of  the  circle. 


0  Q-Q--- 


THREE    PAPULES    IN'   THE 
RADII    OP   THE   CIRCLE. 


^    o    <^ 

Many  circular  lesions  may  occur  close  together,  and  the  tout  ensemble  may  look 
something  like  a  maze  ;  b\it,  if  carefully  studied,  the  circular  arrangement  of  each 
individual  lesion  can  be  easily  made  out. 

As  the  original  papules  may  undergo  certain  transformations,  so  also  may  the 
recurrent  papules.  Some  maj-  be  larger  than  others;  in  some,  necrosis  may  occur, 
with  the  result  that  a  scab  develops.  On  removal  of  the  scab,  if  the  lesion  is  an 
early  one,  a  small  ulcer  may  be  met  with  underneath,  but,  most  frequently,  the 
ulcer  beneath  has  scarred,  and  the  floor  is  covered  with  well  formed  epithelium. 
This  latter  condition  is  rather  characteristic  of  syphilis. 

Another  almost  pathognomonic  feature  of  the  scabbed  recurrent  papule  is,  that 
when  the  scab  is  removed,  the  healed  floor  is  uneven — divided  into  several  loculi — 
and  each  of  these  loculi  is  separated  by  a  tiny  bridge  of  normal  skin. 

Presumably  each  loculus  has  been  a  distinct  le.sion,  but,  when  each  ulcerated, 


140  THE   BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   SYPHILIS. 

a  common  scab  formed  for  all.  These  loculated  scarred  lesions  are  frequently  to 
be  seen  on  the  face,  in  the  naso-facial  and  oro-facial  grooves.  Especialh^  when  they 
occur  in  the  region  of  the  mouth,  almost  certainly  one  or  more  lesions  will  be  met 
with,  one  pole  of  which  will  be  touching  the  mucous  membrane  of  the  lower  lip. 

One  is  frequently  called  upon  to  differentiate  the  facial  scars  which  have 
resulted  from  Lupus  vulgaris  and  from  sj'philis. 

The  tuberculous  scar  is,  as  a  rule,  irregular  in  outline,  sharply  circumscribed, 
and  only  very  slightly  depressed  below  the  surface  of  the  surrounding  skin.  It  is, 
moreover,  even  and  shiny  on  the  surface,  and  not  infrequently  infiltrated  with 
telangiectases,  especially  if  the  lesion  has  been  treated  with  X-rays. 

The  syphilitic  scar,  on  the  other  hand,  is  not  one  flat  scar,  but  an  area  made 
up  of  several  little  ones.  Each  little  scar  is  deeply  depressed,  not  shiny,  and  usualh' 
quite  white.  If  the  organisms,  instead  of  spreading  from  a  papule  here  and  a 
papule  there,  spread  from  those  papules  covering  one  large  area  of  the  skin  ;  should 
they  in  time  develop  their  life-cycles,  the  lesion  formed  will  be  either  a  very 
large  circle,  or  a  segment  of  a  very  large  circle.  This  is  the  so-called  serpiginous 
syphilide.  Characteristic  of  the  serpiginous  syphilide  is  the  red-purple  discoloura- 
tion of  the  skin  in  the  circle. 

The  last  recurrent  skin  lesion  to  be  described  is  the  gumma,  and  the  way  in 
which  a  gumma  is  formed  is,   in  my  opinion,  the  following  : — 

The  distribution  of  the  blood  supply  in  the  skin  is  not  unlike  that  in  the  liver, 
i.e.,  the  skin  is  divided  into  roughly  circular  areas  about  the  size  of  a  shilling. 
There  is  a  venous  ring,  so  to  speak,  in  the  circumference  of  each  circle,  and,  when 
congested,  it  gives  rise  to  circular  purple  patches  with  a  white  centre,  to  which 
the  name  of  (livido)  is  given.  In  the  centre  of  each  circular  area  an  artery  runs, 
and  it  gives  off  branches  as  radii. 

It  is  along  this  central  artery  that  the  organisms  reach  the  skin,  and  it  is  in  the 
walls  of  vessels  that  the  organisms  develop.  Should  the  recurrent  papule  ^e  of  a 
more  pronounced  character  than  those  just  described,  i.e.,  should  the  development  of 
the  organisms  be  on  a  larger  scale,  there  will  be  a  corresponding  increase  of  connective- 
tissue  cells.  As  these  will  be  formed  in  the  walls  of  the  central  artery,  they  may  be 
sufficient  to  occlude  its  lumen.  Occlusion  of  the  lumen  would  result  in  the  loss  of 
blood  supply  to  the  circular  area  affected,  consequently  the  skin  corresponding  to 
this  area  would  necrose,  an  ulcer  would  be  formed,  or,  in  other  words,  a  gumma. 

In  support  of  the  view  just  enunciated,  are  the  pathognomonic  signs  that, 
however  many  gummata  form  in  a  certain  area  of  skin,  each  will  remain  separate, 
they  will  not  coalesce,  and  each  will  be  approximately  the  same  size,  and  the  scar 
resulting  from  the  ulceration  will  have  the  same  diameter  as  the  ulcer  had.     A 


SYPHILIS   OF   THE    SKIN.  141 

point  of  extreme  diagnostic  importance,  and  one  that  should  always  be  borne  in 
mind,  is  the  fact  that  the  Leucoajtozoon  syphilidis  is  not  a  pus-producing  organism, 
therefore  the  lesions  resulting  from  its  development  have,  as  a  rule,  no  circum- 
ferential signs  of  inflammation. 

It  sometimes  happens  that  the  recurrent  rash  is  generalised,  and  indistinguish- 
able from  the  first  eruption.  Such  a  rash  may  or  may  not  be  preceded  by  a  sore 
indistinguishable  from  a  chancre.  The  chancre-like  sore  may  either  appear  on 
the  same  site  as  the  original  sore,  or  elsewhere. 

If  the  recurrent  rash  is  generalised  and  is  not  preceded  by  a  chancre-like  sore, 
it  means  that,  when  the  organisms  first  reached  the  skin  either  the  treatment  or  the 
host's  resistance,  or  both,  were  sufficiently  powerful  to  prevent  the  organisms  from 
spreading  peripherally,  hence  when  they  became  active  again,  they  did  so  in  the 
original  areas  in  which  their  further  progress  was  stopped.  Since  the  salvarsan 
era,  such  recurrences  are  not  uncommonly  seen,  but  before  the  advent  of  this  drug 
they  were  distinctly  rare. 

1  had  one  remarkable  case  before  "  606  "  was  in  use,  which  might  be  recorded  here. 

Case  13. — A  man  aged  54considted  me,  complaining  of  a  rash  and  a  sore  throat. 
The  rash  was  a  typical  maculo-papular  syphilide,  and  its  distribution  was  widespread. 
There  were  multiple  lesions  in  the  mouth,  which  were  mucous  papules.  Every  lesion 
was  discrete,  there  was  no  attempt  at  the  formation  of  circles,  there  was  no  general 
enlargement  of  the  lymphatic  glands,  and  the  patient  had  not  recently  had  a  sore. 

This  patient  had  contracted  syphilis  twenty-three  years  previously,  and  beyond 
the  early  symptoms,  which  simulated  those  of  which  he  now  complained,  he  had 
always  been  in  the  best  of  health,  and  had  never  had  a  recurrence. 

Originally  the  patient  was  treated  for  about  three  years  with  mercury  internally. 

A  recurrent  rash  preceded  by  a  sore  is  a  case  of  auto-reinfection. 

The  rationale  of  the  phenomena  just  mentioned  is  simple. 

When  mercury  was  the  only  anti-syphilitic  drug  in  use,  owing  to  its  slow  action, 
in  most  cases  the  organisms  were  not  vanquished  until  the  host  had  become 
accustomed  to  form  antibodies,  and  to  produce  them  without  necessarily  a  stimulus 
to  do  so.  If  the  check  on  the  antibody  production  occurred  early,  i.e.,  before  the 
production  became  a  habit,  it  is  analogous  to  saying  that  the  patient's  immunity 
against  syphilis  approaches  nullity.  In  such  a  condition,  the  spores  can  wake  up 
again,  when  they  would  give  rise  to  symptoms  indistinguishable  from  those  they 
gave  rise  to  when  their  development  was  checked. 

Since  salvarsan  has  come  in,  owing  to  its  rapid  action,  it  often  happens  that 
the  antibody  production  is  checked,  or,  in  other  words,  the  patient's  immunity  is 
lessened,  hence  the  more  frequent  occurrence  of  a  recurrent  generalised  eruption. 


142  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF    SYPHILIS. 

The  earlier  the  antibody  production  is  checked,  the  less  the  resistance  of  the 
patient  against  the  disease.  Therefore,  the  initial  recurrent  lesion  will  sinudate 
the  lesion  first  developed  by  a  patient,  who  has  never  had  syphilis  before,  and  this 
is  a  chancre. 

Immunity  against  a  disease,  besides  being  variable  in  difTerent  indi-\aduals, 
is  largely  dependent  upon  the  severity  of  the  infection,  and  the  specificity  of  the 
treatment.  AVhat  it  readily  comes  to  is  this,  that  a  ratio  exists  between  the  existen.ce 
of  immunity  and  the  length  of  time  during  which  antibody  production  is  maintained. 
Before  closing  this  chapter,  a  few  more  words  might  be  said  with  advantage, 
regarding  the  differential  diagnosis  of  syphilitic  rashes  from  rashes  of  other  origin, 
which  may  be  confounded  with  them. 

Mention  has  already  been  made  of  varicella  and  lupus,  but  before  mentioning 
other  diseases,  certain  toxic  er\i;hemata  must  be  considered,  as  there  is  a  causal 
relationship  between  some  well  known  types  and  syphilis. 

Syphilis  may  cause  typical  Erythema  nodosum  and  Erythema  multiforme, 
but  as  to  whether  it  ever  causes  purpura,  I  cannot  be  sure. 

The  two  types  of  toxic  erythemata  just  mentioned,  are  indistinguishable  from  those 
types  produced  by  other  causes,  and  they  invariably  occur  early  in  the  generalisation 
stase,  indeed,  sometimes  before  the  true  sy|)hilitic  rash  makes  its  appearance. 

The  other  skin  diseases,  which  are  apt  to  be  confused  with  syphilis,  are 
Pityriasis  rosea,  scabies,  psoriasis.  Erythema  induratmn,  fungus  diseases,  such  as 
sporotrichosis  and  blastomycosis,  certain  drug  eruptions,  especially  the  one  caused 
bv  iodides,  leprosy,  and  various  rare  tuberculides. 

Pityriasis  Rosea. — This  rash  is,  generally  speaking,  limited  to  the  vest  area, 
it  covers  this  area  in  a  few  days  after  the  appearance  of  the  initial  patch,  which  is 
sometimes  called  the  herald  patch,  and  is  scaly  almost  from  the  commencement. 

The  lesions  are  bigger  than  syphilitic  lesions,  they  are  not  so  papular,  those 
on  the  back  run  in  the  direction  of  the  ribs,  a  point  which  often  raises  confusion 
with  syphilis,  but  no  trouble  should  ever  arise  in  differentiating  the  two  diseases, 
if  it  is  borne  in  mind  that  a  syphilitic  lesion  does  not  scale  until  it  retrogresses, 
while  a  lesion  of  Pityriasis  rosea  is  scaly  from  the  beginning. 

A  lesion  of  Pityriasis  rosea  is  red  in  the  circumference,  yellow  in  the  centre, 
the  scales  are  most  evident  at  the  junction  of  these  boundaries,  and  the  scales 
have  their  loose  ends  inwards. 

When  a  svphilitic  lesion  scales,  the  scales  form  in  the  centi-e,  they  are  more 
apparent  and  not  so  sebaceous  as  those  just  described,  and  moreover  they  are  more 
adherent. 

Scabies. — A   very   favourite  localisation   for   scabies  lesions   is   on   the  penis. 


SYPHILIS   OF   THE    SKIN.  143 

where  they  form  papules,  which  at  first  sight  might  suggest  syphiUs.  AVhen 
examined,  the  papules  are  found  not  to  be  infiltrated,  and  burrows,  and  even  the 
acarus  itself  may  be  found.  Itching,  and  finding  similar  lesions  elsewhere,  namely, 
on  the  buttocks,  wrists,  and  in  between  the  fingers,  clinches  the  diagnosis. 

Psoriasis. — From  a  naked-eye  examination  of  the  lesions,  it  may  in  some  cases 
be  absolutely  impossible  to  distinguish  between  psoriasis  and  syphilis.  In  such 
cases  one  has  to  rely  upon  history,  and  to  note  whether  the  scales  when  removed 
reveal  bleeding  points,  a  phenomenon  which  is  typical  of  psoriasis  only. 

Many  patients  with  psoriasis  have  either  had  the  complaint  for  years,  or  have 
had  recuiTences  of  it,  and  often  another  member  of  the  family  is  subject  to  the 
disease.  A  squamo-papular  syphilide  resembling  psoriasis,  is  a  recurrent  syphilide, 
therefore  every  lesion  should  be  thoroughly  examined  to  see  if  any  of  them  are 
circular  or  gyrate  in  form,  because  if  so  they  are  certainly  syphilitic. 

An  examination  of  the  scalp  should  always  be  undertaken,  since  psoriasis  very 
commonly  affects  the  scalp,  while  a  squamo-papular  syphilide  does  so  rarely. 

Psoriasis  may  affect  the  penis  only,  and  so  may  lichen  planus,  in  which  case 
the  lesions  are  usually  on  the  glans.  The  type  of  Lichen  planus  which  affects  the 
glans  penis  is  the  circinate  form,  but,  from  its  smallness  and  its  perfect  regular  outline, 
it  ought  never  to  be  mistaken  for  syphilis. 

Erythema  induratum. — This  condition  is  a  tuberculide  and  practically  affects 
only  girls  between  the  ages  of  15  and  24.  The  lesions  usually  affect  both  legs 
and  are  situated  on  the  posterior  aspects.  The  initial  lesion  is  a  red  patch,  this 
becomes  a  purple  coloured  papule,  and  later  the  centre  breaks  down  to  form  a  deep 
crateriform  ulcer.  The  only  sj'philitic  lesion  it  could  possibly  be  confounded  with 
would  be  a  gumma,  but,  as  I  have  already  stated,  a  gumma  is  an  ulcer  the  size  of 
which  exactly  corresponds  to  the  area  affected,  hence  the  term  crateriform  could 
never  be  applied  to  it. 

Sporotrichosis,  blastomycosis,  and  oriental  Sore  can  only  satisfactorily  be 
diagnosed  by  demonstrating  the  specific  organism,  either  in  culture,  film,  or  section, 
made  from  the  lesion  in  question. 

An  iodide  rash  is  most  likely  to  be  confused  with  a  papulo-pustular  syphilide, 
which  is  an  early  syphilitic  eruption,  hence  other  signs  and  symptoms  of  the  disease 
will  generally  be  found  on  a  further  examination.  An  iodide  rash  disappears  very 
quickly  on  suspension  of  the  drug. 

Difficult  tuberculides  are  best  diagnosed  by  the  way  they  react  to  tuberculin. 

If  every  reader  will  bear  in  mind  the  few  points  mentioned  in  this  chapter,  and 
then  confirm  them  on  clinical  material,  I  think  he  will  soon  agree  with  me  in  stating 
that,  of  all  skin  diseases,  the  various  syphilitic  eruptions  are  the  easiest  to  diagnose. 

K 


CHAPTER  XV. 
SYPHILIS   OF  THE   LYMPHO-  AND  HAEMOPOETIC  SYSTEMS. 

The  organisms  from  the  site  of  infection  soon  reach  the  local  lymphatics,  and 
spread  along  them  into  the  nearest  chain  of  lymphatic  glands. 

The  lymphangitis  may  be  marked  enough  to  cause  occlusion  of  the  vessel, 
when  a  hard  cord  may  be  felt  running  along  the  dorsum  of  the  penis. 

The  lymphangitis  may  be  more  marked  in  some  areas  than  in  others,  along 
its  course,  which  on  palpation  may  feel  like  a  chain  of  beads.  One  bulging  only 
may  be  present,  or  several. 

Lymphatics,  other  than  those  running  along  the  dorsum  of  the  penis,  may  be 
affected  in  the  same  way.  If  the  lymphangitis  is  widespread,  oedema  of  the  whole 
skin  of  the  penis  may  result. 

Oedema  of  the  skin  of  the  penis  is  most  marked  when  the  sore  is  in  the  corona. 
The  sore  may  often  be  hidden,  because  the  foreskin  cannot  be  drawn  back,  but  a 
hidden  chancre  can  always  be  diagnosed,  if  it  be  remembered  that  such  an  oedema 
is  non-inflammatory,  i.e.,  not  red  and  painful,  as  it  is  in  soft  sore  and  gonococcal 
infections. 

During  the  stage  of  the  generahsation  of  the  virus,  all  the  lymphatic  glands 
become  impHcated,  but  the  set  which  is  always  most  enlarged  is  that  draining  the 
site  of  the  primary  sore.  This  point  will  often  enable  one  to  locaHse  a  sore,  ^which 
has  escaped  notice  during  the  first  examination. 

Owing  to  the  richness  of  the  lymphatic  vessels  draining  the  mucous  membrane 
of  the  mouth,  any  sore  in  this  region  is  always  accompanied  by  an  enormous 
enlargement  of  the  glands  in  the  neck. 

As  lymphatics  cross  the  middle  line  of  the  body,  the  enlargement  of  the  glands 
on  the  opposite  side  to  that  on  which  the  sore  is  situated  may  be  greatest.  Syphihtic 
lymphatic  glands  are  hard  and  discrete,  or  enlarged,  matted  together  and  soft.  The 
degree  of  enlargement  varies  enormously  in  the  different  cases.  As  a  rule,  it  may 
be  said  that,  the  greater  the  enlargement,  the  better  the  protective  capacity  of 
the  host  against  the  parasite,  and  vice  versa. 


SYPHILIS   OF   THE   LYMPHO-    AND    HAEMOPOETIC    SYSTEMS.  145 

It  must  always  be  remembered  that  cocci  usually  accompany  the  syphilitic 
parasites  along  the  lymphatics  into  the  glands,  with  the  result  that  they  may  at 
any  time  multiply  and  cause  acute  inflammation.  Acute  inflammation  causes 
the  lymphatic  glands  to  become  glued  together,  and  one  or  more  of  them  may 
suppurate,  and  simulate  the  bubo  so  common  in  the  soft  sore  infection.  Generally 
speaking,  the  only  glands  which  suppurate,  in  syphilis,  are  those  draining  the  site  of 
the  initial  lesion,  and  the  glands  iu  the  neck.  The  reason  why  the  glands  in  the 
neck  not  infrequently  suppurate  is,  because  of  the  lymphangitis  which  results  from 
the  early  mucous  membrane  lesions  in  the  mouth,  and  as  the  mouth  is  exposed  to 
the  air,  and  always  crowded  with  pus-producing  organisms,  some  of  these  find  easy 
entrance  into  the  lymphatic  glands,  in  which  they  can  cause  suppuration. 

Suppuration  in  these  lymphatic  glands,  although  most  common  during  the 
acute  stage  of  the  disease,  may  commence  long  after  all  the  syphihtic  symptoms 
have  vanished.  The  lymphatic  glands  may  also  be  the  seat  of  recurrent  syphihtic 
lesions,  and  gummata  not  infrequently  afi'ect  the  cervical  set. 

The  diffuse  papular  syphilitic  eruption  which  is  so  commonly  seen  on  the  penis, 
in  the  neighbourhood  of  the  primary  sore,  and  is  usually  well  marked  before  any 
signs  of  a  rash  have  occurred  elsewhere,  doubtless  arises  from  a  spread  of  the 
organisms,  from  the  site  of  infection,  along  the  lymphatics. 

Late  syphilitic  lymphangitis  is  very  rare,  but,  having  had  a  case  under  my 
care,  a  report  of  it  here  would  not  be  out  of  place. 

Case  14. — A  man  now  aged  46  contracted  syphihs  in  1882.  His  first  recurrence 
was  a  papular  syphihde  of  the  right  pahu,  in  1890.  The  next  recurrence  was  a  ser- 
piginous syphihde  on  the  left  half  of  the  scrotum,  and  another  on  the  gluteal  region 
on  the  same  side,  in  1900. 

A  year  later,  the  scrotum  first  on  the  affected  side,  and  in  time  as  a  whole, 
began  to  enlarge. 

On  examination,  1911,  the  syphilides  had  disappeared,  the  scrotum  was 
28|  inches  in  circumference,  and  was  somewhat  eczematous  on  the  surface.  The 
swelhng  appeared  to  be  in  the  skin,  which  was  hard,  barely  oedematous,  and 
retained  its  rugose  appearance.  The  testicles  could  not  be  felt.  The  patient  had 
also  chronic  superficial  glossitis.  As  a  result  of  thirteen  intramuscular  injections  of 
grey  oil,  the  circumference  of  the  scrotum  was  reduced  to  13i  inches,  the  skin  became 
softer,  the  swelhng  of  the  penis  disappeared,  and  the  testicles,  which  appeared 
normal,  could  be  felt  underneath.  I  saw  this  patient  again,  two  years  later,  and 
his  scrotum  was  then  nearly  normal  in  size. 

Syphilis  as  a  direct  cause  of  elephantiasis,  a  name  which  coidd  be  easily  given 
to  the  condition  just  described,  is,  as  I  have  already  stated,  exceedingly  rare,  but 

k2 


14:6  THE   BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

the  elepliantiasic  condition  following  gummata  and  such  deep-seated  mischief  as 
periostitis,  is  not  uncommon.  The  direct  cause,  in  the  former,  is  a  secondary 
infection  ;  and  in  the  latter,  mechanical  obstruction. 

In  the  case  just  reported,  the  swelhng  of  the  scrotum  started  some  time  after 
the  serpiginous  syphihde  had  disappeared,  and  therefore  could  not  be  secondary 
thereto.  There  was  no  iilceration,  therefore  a  coccal  infection  was  unable  to  play 
a  part. 

A  neglected  chapter,  in  the  chnical  story  of  syphilis,  is  phlebitis.  Veins  are 
infected  with  the  organism  of  syphiUs  much  more  frequently  than  is  supposed  to  be 
the  case.  In  my  experience,  the  veins  most  often  affected  are  those  of  the  upper 
and  lower  extremities,  especially  those  of  the  latter. 

Syphihtic  phlebitis  of  both  arms,  or,  more  commonly,  of  only  one,  causes 
congestion  in  the  fingers.  The  congestion  may  come  and  go,  with  the  result  that 
the  diagnosis  of  Kaynaud's  disease  is  usually  made.  When  the  legs  are  affected, 
and  again  it  is  usually  only  one  leg  that  is  involved,  it  is  nearly  always  the  internal 
saphenous  vein  that  is  thrombosed.  As  the  condition  is  typical  of  the  infection 
which  caused  it,  and  as  the  descriptions  of  it  are  so  scanty,  it  may  be  well  to 
describe  two  typical  cases,  which  I  have  had  under  my  care. 

Case  15. — A  woman  had  a  sore  in  July,  the  eruption  commenced  in  September, 
when  treatment  was  started.  In  December,  patient  complained  of  severe  pain  on 
the  inner  side  of  the  thigh.  There  was  nothing  to  be  seen,  but,  on  palpation,  one 
could  feel,  in  the  line  of  the  internal  saphenous  vein,  about  l-J  inches  above  the 
knee,  a  hard,  tender,  spindle-shaped  swelhng,  roughly  1  inch  in  length. 

As  time  went  on,  this  swelhng  came  gradually  nearer  to  the  surface,  and  finally 
ulcerated.  Papules  developed  along  the  course  of  the  vein,  both  above  and  below 
the  ulcer. 

"  Nodules  "  of  phlebitis  were  also  found  in  both  legs,  and  some  of  them  had 
come  to  the  surface  and  ulcerated.  * 

Cose  16. — A  man  aged  36,  no  history  of  syphihs,  sought  advice  for  acute  pain 
and  swelhng  of  his  right  leg.  He  had  several  attacks  of  this  pain  and  swelhng, 
and  occasionally  the  whole  foot  became  quite  blue.  No  diagnosis  was  at  this  time 
made.  While  these  periodic  swellings  of  the  leg  were  taking  place,  the  patient  on 
two  occasions  had  a  pulmonary  embolus,  and  on  each  occasion  very  nearly  lost 
his  life.  The  patient  frequently  complained  of  very  bad  headaches,  and  often 
felt  sick  and  giddy.  The  next  step  in  the  case  was  the  appearance  of  very  painful 
red  nodules  in  the  skin.  These  nodules  were  much  longer  than  they  were  broad, 
they  were  surrounded  by  inflammation,  and  they  commenced  in  the  internal 
saphenous  vein  and  gradually  descended  along  all  its  branches,  until  the  toes  were 


SYPHILIS    OF   THE    LYxMPHO-    AND   HAEMOPOETIC   SYSTEMS.  147 

reached.     Under  appropriate  anti-sypliilitic  treatment  the  patient  made  a  good 
recovery. 

Venous  lesions  may  occasionally  be  the  first  signs  of  the  generalisation  of  the 
virus,  and  they  are  therefore  jDrobably  toxic  in  origin. 

Such  lesions  may  give  rise  to  symptoms  and  signs  which  closely  simulate  two 
well  known  clinical  conditions  :   (a)  Erythema  nodosum  ;   (6)  Erythema  multiforme. 

Neither  of  these  can  be  distinguished  from  the  same  chnical  condition,  produced 
by  other  causes.  Erythema  nodosum  syphilitica  simulates  exactly  the  chnical 
condition  which  so  frequently  accompanies  rheumatic  fever,  and  it  occurs  in  the 
same  situation,  namely,  on  the  anterior  surfaces  of  both  legs.  The  same  applies 
to  Erythema  multiforme  syphilitica,  which  affects  most  commonly  the  dorsimi  of 
the  hands. 

Since  the  leucocytozoon  pervades  every  nook  and  crevice  in  the  body,  by  means 
of  the  blood  stream,  and  since  the  organism  has  a  predilection  for  the  walls  of 
vessels,  in  which  to  carry  out  its  life-cycle,  it  is  not  to  be  wondered  at  that  syphilitic 
arterial  lesions  are  common.  Any  lesion  in  the  wall  of  an  artery  is  liable  to  lead 
to  an  endarteritis,  which  is  certain  to  occlude  the  vessel,  if  it  be  small,  hence  the 
blood  supply  to  the  area  fed  by  this  vessel  will  be  cut  off. 

There  are  some  arteries  which  are  more  frequently  involved  than  others.  The 
arteries  which  make  up  the  circle  of  Willis  are  those,  an  affection  of  which  gives  rise 
to  symptoms,  often  within  a  few  months  of  the  time  of  infection.  The  commonest 
cerebral  arterial  lesion  is  one  which  gives  rise  to  a  hemiplegia.  The  hemiplegia 
is  usually  unilateral.  An  early  syphihtic  monoplegia  is  very  rare.  Later  in  the 
course  of  the  disease,  the  anterior  artery  of  the  cord  becomes  involved,  and  gives 
rise  to  myelitis.  Later  still,  the  affected  arteries  undergo  a  lipoid  degeneration, 
with  the  result  that  the  vessel  gives  way,  an  aneurysm  may  be  formed,  and  the 
patient  dies  of  haemorrhage. 

The  cerebral  vessels,  again,  are  those  most  commonly  affected,  and  the  arch 
of  the  aorta  is  a  frequent  victim. 

The  main  feature  diflterentiating  syphilitic  arteritis  from  other  forms  of 
arteritis,  is  the  marked  localisation  of  the  trouble.  The  whole  of  the  arch  of  the  aorta 
may  be  diseased,  and  yet  the  descending  and  abdominal  aorta  may  be  natural. 
Syphilitic  aortitis  is  markedly  different  from  that  form  met  with  in  general  arterio- 
sclerosis resulting  from  other  causes. 

Lipoid  degeneration  is  a  pathognomonic  feature  of  syphilitic  aortitis,  hence 
the  calcareous  plates,  so  commonly  seen  in  the  other  forms,  are  absent. 

Any  disease  of  the  aorta  naturally  causes  an  increased  blood  pressure  and  an 
accompanying  general  arteriosclerosis,  therefore  a  typical  case  of  syphilitic  aortitis 


148  THE   BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT    OF   SYPHILIS. 

may  be  met  with,  in  which  the  other  vessels  may  exhibit  the  changes  commonly 
seen  in  ordinary  arteriosclerosis. 

Late  syphilitic  lesions  are  characterised  by  the  lipoid  degeneration  undergone 
by  the  cells  in  the  afEected  area.  The  lipoid  formed  by  these  cells  is  of  the  nature 
of  a  protective  substance,  and  it  is  largely  responsible  for  the  strong  positive  Wasser- 
mann  reactions  to  be  met  with  in  these  arterial  cases. 

This  lipoid  material  fixes  itself  on  to  the  globulin  molecules,  and,  in  so  doing, 
robs  these  molecules  of  some  of  the  ions  which  are  attached  to  them.  The  salts 
most  easily  displaced  are  the  calcium  salts,  hence  the  explanation  of  the  absence 
of  the  calcareous  plates  in  S3'philitic  aortitis. 

Andrewes^  has  done  some  very  interesting  and  important  work  in  this  connection. 
He  incinerated  several  diseased  aortae,  estimated  the  calcimn  in  the  ash,  and  found 
that  the  calcimn  content  of  syphilitic  aortae  was  far  and  away  below  that  of  aortae 
diseased  from  other  causes. 

In  some  cases  of  syphilitic  aortitis,  Andrewes  also  estimated  the  calcium  content 
of  the  aorta  away  from  the  syphilitic  lesion,  and  found  that  not  infrequently  the 
calcium  content  was  very  much  raised. 

This  work  of  Andrewes  proves  that  the  syphilitic  process  is  quite  localised, 
and  that  the  vessels  elsewhere  may  show  the  signs  of  ordinary  arteriosclerosis. 
Aneurysm  need  not  necessarily  be  a  late  syphilitic  lesion,  as  I  have  seen  two  cases 
of  popHteal  aneurysm,  of  which  one  occurred  four  years,  and  the  other  five  years 
after  infection.  I  remember  another  case  in  which  a  bilateral  popliteal  aneurysm 
occurred  seven  years  after  infection,  and  I  have  notes  of  a  case  of  an  aneurysm 
of  the  arch  of  the  aorta,  in  a  congenital  sjrphilitic  girl  aged  15. 

Syphilis  of  the  heart,  in  the  early  stages,  doubtless  occurs  more  often  than  is 
thought  to  be  the  case,  but  unfortunately  it  cannot  be  diagnosed  with  certainty. 

The  early  sj-phihtic  lesion  of  the  heart  is  a  diffuse  myocarditis.  As  a  rule,  no 
enlargement  can  be  ascertained,  and  in  two  well  marked  cases — which  I  had  imder 
care — the  only  symptoms  and  signs  which  the  patients  had,  were  cardiac  embarrass- 
ment and  a  quick  pulse.  By  cardiac  embarrassment,  I  mean  difiiculty  in  breathing 
on  stair  climbing  or  on  any  exei-tion,  and  pronounced  sweating.  Sternal  pain 
is  not  an  uncommon  symptom  ;  pain  on  palpation  of  the  cardiac  area  is  also 
experienced,  and  occasionally  an  accentuation  of  the  systolic  sound  over  both  the 
aortic  and  puhnonary  orifices  can  be  easily  detected.  In  a  few  cases,  the  area  of 
cardiac  dullness  is  found  to  be  enlarged. 

No  case  can  be  diagnosed  correctly  until  treatment  has  been  prescribed,  and 
any  alteration  of  symptoms  has  been  noted.  Late  syphiUtic  lesions  of  the  heart 
are  locahsed  lesions,  therefore  the  sjmiptoms  will  vary  according  to  the  site  affected. 


SYPHILIS   OF   THE   LYJIPHO-    AND    HAKMOPOETIC    SYSTEMS.  149 

A  gumma  of  the  heart  may  exist,  and  heal  without  ever  giving  rise  to  symptoms, 
but  if  the  gumma  is  situated  in  His's  bundle,  which  is  not  an  uncommon  site, 
symptoms  arise  which  are  almost  pathognomonic,  and  to  which  the  name  of  heart- 
block  is  given. 

A  lesion  of  the  bundle  of  His  will  naturally  cause  an  alteration  in  the  way  the 
impulse  travels  along  the  cardiac  muscle  fibres,  and  this  alteration  in  most  cases 
can  only  be  detected  by  an  electro-cardiographic  tracing.  Should  the  lesion  be 
severe  enough  to  cause  spiiptoms,  the  patient  will  seek  advice  for  periodic  attacks 
of  giddiness,  with  maybe  temporary  loss  of  consciousness.  Stoke-Adams  symptoms 
may  occasionally  be  met  with,  and  usually  the  pulse  rate  is  slow. 

A  slow  pulse,  i.e.,  between  .30  and  50  in  a  young  subject,  should  always  make 
the  observer  suspect  a  syphilitic  cardiac  lesion.  A  physiological  brachycardia  is 
extremely  rare,  the  best  known  instance  is  that  of  Napoleon  who  was  always  said 
to  have  had  a  normal  pulse  rate  of  40. 

A  syphihtic  myocarditis  of  the  left  ventricle  may  give  rise  to  symptoms  of 
cardiac  asthma,  but,  since  asthma  is  so  frequently  reheved  by  potassium  iodide,  it 
is  extremely  difficult  to  make  a  correct  diagnosis. 

It  should  not  be  forgotten  that  the  cardiac  sympathetic  nerves  are  not  at  all 
infrequently  involved,  in  cases  of  degenerative  myelitis,  and,  if  the  symptoms 
produced  are  at  all  severe,  the  physician's  attention  may  be  drawn  to  the  heart 
only,  with  the  result  that  the  true  nature  of  the  trouble  is  overlooked.  To  cite 
a  case. 

Case  17. — A  man,  aged  37,  who  had  contracted  syphilis  eight  years  pre\aously, 
came  to  me  complaining  of  attacks  of  shortness  of  breath,  giddiness,  and  a  feeling 
as  if  he  were  going  to  faint.  He  had  previously  suffered  from  very  bad  attacks 
of  coughing,  for  which  a  throat  specialist  had  snipped  off  a  piece  of  his  uvula.  The 
patient  still  had  attacks  of  coughing,  and  he  often  felt  very  sick. 

On  careful  examination,  one  could  plainly  see  that  it  was  a  typical  case  of 
degenerative  myelitis,  as  many  of  the  other  cardinal  symptoms  were  present. 

As  time  went  on,  the  sickness  developed  into  typical  gastric  crises,  and  the 
cardiac  condition  became  very  much  worse.  The  patient  would  suddenly  swoon 
away,  and  become  quite  unconscious  ;  his  complexion  would  become  blue,  and  then 
ashen  grey,  and  for  a  short  interval  his  pulse  could  not  be  felt.  Anti-syphilitic 
treatment  aggravated  the  cardiac  crises  very  much  indeed. 

The  relationship  between  Raynaud's  disease  and  sj^^hilis  has  always  excited 
a  great  deal  of  discussion,  consequently  opinions  vary  on  the  point.  I  have 
absolutely  no  doubt  that  Raynaud's  phenomena  can  occur  in  congenital  syphilis, 
and  be  due  to  the  syphilis.     Its  occasional  association  with  haemoglobinuria,  not  to 


150  THE   BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

mention  those  cases  in  which  the  Wasseriiiann  reaction  is  positive,  is  quite  sufficient 
evidence,  since  spasmodic  haemoglobinuria  is  almost  invariably  due  to  syphilis. 

When  Raynaud's  phenomena  are  said  to  occur  in  adults,  more  otten  than  not, 
they  are  not  the  true  phenomena  of  what  is  called  Raynaud's  disease.  Some  of 
the  cases  in  which  recurrent  local  asphyxia  of  the  fingers,  and  maybe  of  the  toes 
occurs,  are  really  cases  of  syphilitic  phlebitis.  Syphilis  may  be  a  predisposing  cause 
of  Raynaud's  disease  in  the  adult,  just  as  any  other  protozoal  disease  may  be.-  ^ 

We  have  now  to  discuss  the  blood  changes  which  usually  occur  in  sj'philis. 
The  true  blood  changes  affect  only  the  leucocytes,  since  it  is  only  in  those  cases 
in  which  syphilis  has  caused  an  anaemia,  that  changes  are  to  be  found  in  the  red 
blood  corpuscles,  and  then  the  changes  are  typical  of  ordinary  secondary  anaemia. 
Syphilitic  anaemia,  owing  to  the  use  of  salvarsan,  is  not  now  often  met  with,  and, 
in  many  of  those  cases  in  which  it  did  occur,  it  was  often  aggravated  by,  if  not 
actually  caused  by  the  mercurial  treatment.  Hence  the  reason  for  stating  that 
changes  in  the  red  blood  corpuscles,  such  as  are  to  be  sometimes  met  with 
in  syphilis,  are  generally  only  secondary  in  nature,  and  not  changes  actually  pro- 
duced by  the  syphilitic  organism  itself. 

The  changes  in  the  leucocytes  are  very  interesting  and  very  important.  In 
early  syphilis,  the  total  number  of  leucocytes  is  increased.  Before  treatment  is 
commenced,  the  relative  increase  of  the  polymorphonuclear  leucocytes  is  greater 
than  that  of  the  lymphocytes  ;  a  ratio  between  the  two  exists,  and  it  is  dependent 
upon  the  severity  or  lightness  of  the  case.  In  the  severe  cases,  the  relative  increase 
of  the  neutrophile  leucocytes  is  very  much  greater  than  that  of  the  lymphocytes — 
indeed,  the  total  number  of  the  lymphocytes  may  be  diminished.  In  light  cases, 
the  percentage  of  lymphocytes  may  approximate  to  the  number  given  by  the  poly- 
morphonuclears, and  may  even  exceed  it. 

Treatment  very  quickly  diminishes  the  percentage  of  the  neutrophiles,  and 
increases  the  percentage  of  the  lymphocytes.  Salvarsan  is  much  more  powerful 
in  this  respect  than  mercury. 

The  lymphocyte  count  may  approximate,  in  early  cases  of  syphilis,  to  60  per  cent. 
Occasionally  a  small  rise  in  the  eosinophiles  is  to  be  met  with,  but  there  appears 
to  be  no  relationship  between  the  eosinophile  count  and  the  kind  of  case.  According 
to  Hazen,*  from  whose  pioneer  work  in  this  field  most  of  these  details  are  taken, 
there  is  no  alteration  in  the  large  mononuclears  or  basophiles.  Curiously  enough, 
the  total  increase  of  leucocytes  is  greater  in  the  negro,  and  the  relative  lymphocyte 
count  is  higher  also,  than  in  the  white  man. 

In  severe  cases,  the  lymphocyte  count  is  low  in  comparison  with  the  lymphocyte 
count  in  the  mild  cases,  and,  in  those  cases  which  are  going  to  do  well  under 


SYPHILIS   OF   THE    LYMPHO-    AND    HAEMOPOETIC    SYSTEMS.  ]  51 

treatment,  the  lymphocyte  count  becomes,  as  a  rule,  very  much  higher  than  in  those 
cases  which  are  not  going  to  do  well.  Hence,  from  a  lymphocyte  chart,  a  prognosis 
can  be  made. 

Mercury  administered  to  normal  men  causes  a  rise  in  the  absolute  and  relative 
lymphocyte  count,  but  a  slight  fall  in  the  total  leucocyte  count ;  therefore  the 
main  decrease  is  in  the  relative  neutrophile  count. 

In  the  second  and  third  years  after  treatment,  the  total  leucocyte  count  is 
only  slightly  raised,  and  the  main  increase  affects  the  lymphocytes.  In  the  late 
stages  of  the  disease,  the  same  picture  is  to  be  found,  and,  in  cases  in  which  treatment 
is  prescribed,  the  absolute  and  relative  lymphocyte  count  increases.  As  a  rule, 
after  the  second  year,  whether  the  patient  is  under  treatment  or  not,  there  is  no 
increase  in  the  eosinophile  count. 

Another  interesting  point  which  Hazen  brings  out,  is  that  males  show  a 
slightly  greater  increase  in  the  total  count  than  do  females,  and  that  females  show 
a  higher  l3^mphocyte  count  than  do  males. 

No  relationship  exists  between  the  lymphocyte  count  and  the  degree  of 
enlargement  of  the  lymphatic  glands,  a  point  which  supports  my  view  that  the 
lymphocytes  manufactured  in  the  lymphatic  glands  remain  in  the  glands,  and  that  those 
which  reach  the  circulation  emanate  from  the  bone-marrow  {vide  Chapter  XLVI). 

From  these  few  remarks  on  the  blood  picture  to  be  met  with  in  syphilis,  the 
reader  will  at  once  observe  how  important  the  lymphocytes  are,  and  how  relatively 
unimportant  are  the  polymorphonuclear  leucocytes,  a  point  which  clearly  shows 
that  phagocytosis  does  not  play  a  great  part  in  bringing  about  the  destruction  of 
the  syphilitic  parasite.  Probably  one  of  the  reasons  why  syphilis  is  not  such  a 
severe  disease  in  women  as  it  is  in  men,  is  due  to  the  higher  lymphocytosis  in  the 
former — after  all,  it  is  from  the  lymphocytes  that  the  protective  substances  of  the 
host  originate.  The  reagin  in  the  Wassermann  reaction  comes  from  the  lympho- 
cytes. Considering  how  chronic  a  disease  syphilis  is,  and  what  a  call  it  makes 
upon  the  lymphocytes  of  the  host  it  attacks,  it  is  not  to  be  wondered  at  that  the 
manufacture  of  the  lymphocytes  becomes  abnormal,  and  that  various  kinds  of 
lymphocytomata  arise,  although  the  syphilitic  parasite  may  have  been  driven  out  of  the 
system.  A  full  exposition  of  this  part  of  the  subject  will  be  found  in  Chapter  XLVI. 
Here  it  may  simply  be  stated  that  syphilis  is  sometimes  the  cause  of  both  leucaemic 
and  aleucaemic  lymphocytomata,  and  very  occasionally  of  pernicious  anaemia. 

'  Andrewes  (1914),  "  Local  Government  Board  :    Report  of  the  Medical  Officer." 
-  Parkes  Weber  (1909),  "  Trans.  Med.  Soc.  Lond.,"  sxxii,  370. 
»  Osier  (1900),  "John  Hopkins  Hosp.  Bull.,"  xi,  41. 
*  Hazen  (1913),  "  Journ.  Cut.  Dis.,"  sxxi,  618. 


CHAPTER  XVI. 
SYPHILIS  OF  THE  MALE  GENITO-URINARY  TRACT. 

Kidneys. 

In  most  cases  of  syphilis,  during  the  acute  stage,  protein  can  be  demonstrated 
in  the  urine.  Hitherto  this  protein  has  always  been  considered  to  be  albumin, 
with  the  result  that  the  kidneys  were  considered  to  be  affected,  and  the  patient 
was  said  to  have  nephritis. 

The  protein  in  the  urine  is  usually  increased  when  mercury  is  given,  hence  it 
was  assumed  that  mercury  had  an  injurious  action  upon  the  kidneys.  If  the 
protein  content  of  the  urine  appeared  to  be  at  all  high,  salvarsan  was  said  to  be 
contraindicated.  Although  there  may  be  an  increase  of  albumin  in  the  urine  in 
early  syphilis,  the  main  protein  increase  in  the  pronounced  cases  is  globulin  or 
lipoid-globulin,  and  the  albumin  content  is  usually  negligible.  Jlercury  increases 
this  globulin  excretion.  SalVarsan  at  first  increases  it,  but  afterwards  very 
quickly  reduces  it,  till  no  protein  is  demonstrable. 

The  globulin,  or  lipoid-globulin,  comes  from  the  blood,  and  not  from  the  kidney 
cells.  It  is  excreted  through  the  glomeruli.  Therefore,  the  presence  of  protein  in 
the  urine  does  not  necessarily  mean  that  the  patient  is  suffering  from  nephritis.  Its 
temporary  increase  after  mercury,  is  due  to  the  fact  that  mercury  stimulates  the  cells 
to  form  protective  substances,  which  circulate  in  the  serum  as  lipoid-globulins,  and 
so  more  is  likely  to  be  excreted.  Hence,  protein  in  the  urine  does  not  signify  that 
mercury  has  an  injurious  action  upon  the  kidneys.  This  temporary  increase  and 
rapid  decrease,  after  salvarsan,  is  due  to  the  fact  that  the  first  action  of  salvarsan 
is  to  increase  the  production  of  lipoid-globulin,  and  then  to  break  it  up.  Hence 
salvarsan  is  not  contraindicated  in  these  cases. 

The  kidney  cells  are  undamaged,  as  no  blood  or  casts  are  to  be  found  in  the 
urine. 

The  following  method  of  examining  the  urine  is  the  best : — 

If  there  is  any  protein  at  all,  a  drop  or  two  of  a  saturated  solution  of  salicyl- 
sulphonic  acid,  added  to  the  urine,  will  cause  a  precipitate.     If  the  precipitate  is 


SYPHILIS   OF  THE    MALE    GENITO-URIXARY   TRACT.  153 

abundant  and  flocculent,  the  chances  are  that  the  protein  is  mainly  globulin  or 
lipoid-globulin.  If  the  urine  contains  globulin  or  lipoid-globulin,  a  piecipitate  will 
be  formed  when  a  few  drops  of  a  5  per  cent,  solution  of  potassium  ferrocyanide 
are  added,  after  the  urine  has  been  acidified  with  a  drop  or  two  of  a  30  per  cent, 
solution  of  acetic  acid.  All  the  globulin,  or  lipoid-globulin,  can  be  precipitated 
with  a  saturated  solution  of  ammonium  sulphate.  The  urine  can  then  be  filtered, 
and  the  albumin  estimated  by  precipitation  with  magnesium  sulphate.  IVIicro- 
scopic  examination  of  the  urine  should  be  made,  and  if  there  are  refractile  colloidal 
particles,  the  urine  contains  lipoid-globulin. 

In  my  opinion,  true  early  syphilitic  nephritis  is  very  rare.  To  my  knowledge,  I 
have  seen  only  one  severe  case.  The  patient  was  thin  and  emaciated.  He  complained 
of  pain  in  both  kidney  regions,  he  had  frequency  of  micturition,  and  there  were 
casts,  blood,  and  albumin  in  the  urine,  but  only  a  trace  of  globulin. 

Globulinuria  may  also  occur  in  late  syphilis,  alone  or  with  p.seudo-chylous 
ascites.  More  lipoid  is  attached  to  the  globulin  in  these  cases,  than  is  the  case  in 
early  syphilis.  Therefore,  the  colloidal  particles  are  larger,  and  display  greater 
optical  activity. 

A  trace  of  globulin  may  be  found  in  those  weird  but  rare  cases  of  progressive 
late  sjrphilitic  nephritis.  The  nephritis  starts  without  the  patient's  knowledge,  and 
may  progress  for  years,  causing  no  symptoms,  until  blood  is  noticed  in  the  urine 
If  the  urine  be  carefully  examined  in  these  cases,  it  will  be  found  that  the  main 
protein  increase  is  albumin,  and  blood  cells  and  casts  are  nearly  always  to  be  seen. 
These  cases  do  only  fairly  well  under  treatment,  and  they  have  to  be  treated 
generally  like  ordinary  cases  of  nephritis,  as  regards  diet,  &c. 

If  allowed  to  progress,  these  cases  of  parenchjTnatous  nephritis  or  large  white 
kidney  begin  to  exhibit  marked  interstitial  changes.  The  connective-tissue  con- 
tracts, causes  degeneration  of  the  kidney  cells,  and  the  end  is  an  irregularly  shaped 
contracted  kidney.  I  should  mention  here  that  salvarsan  is  badly  borne  by  these 
patients,  and  mercury  should  be  used  with  caution,  and  its  administration  regulated  by 
frequent  examinations  of  the  urine.    Iodides  are  indicated  more  than  any  other  drug. 

Chronic  interstitial  nephritis  may  be  caused  by  sj'philis,  but  it  is  usually  only 
one  of  the  sjniiptoms  of  a  generalised  arteriosclerosis. 

Amyloid  disease  may  supervene  upon  some  of  the  acute  cases,  but  this  com- 
plication is  more  often  written  about  than  seen. 

Bladder. 

It  is  only  recently  that  attention  has  been  paid  to  syphilis  of  the  bladder,  but, 
in  the  short  time,  a  number  of  cases  have  been  collected. 


15i  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF    SYPHILIS. 

Naturally,  the  symptoms  will  not  differ  from  those  produced  by  other  factors 
which  cause  cystitis.  lu  the  stage  of  generalisation  of  the  virus,  mucous  papules 
may  occur,  but  they  seldom  give  rise  to  symptoms.  There  may  be  a  slight  frequency 
of  micturition,  and  an  excess  of  a  mucinoid  substance  in  the  urine.  This  mucinoid 
substance  quickly  becomes  precipitated  as  clouds,  when  the  urine  is  allowed  to 
stand.  It  is  soluble  in  acetic  acid,  and  it  reduces  Fehling's  solution.  It  is  found 
in  most  cases  of  cystitis,  whatever  be  the  origin  of  the  inflammation.  In  the  late 
stages  of  syphilis,  gummatous  ulceration  and  papillomatous  growths  have  been 
described.^  ^  ■^  *  WTienever  ulceration  of  the  bladder  is  diagnosed  by  a  cystoscopic 
examination,  syphilis  should  alw-ays  be  considered,  since  the  progress  is  so  good, 
if  syphilis  is  the  cause,  as  the  cases  respond  at  once  to  treatment. 

Testicles. 

Early  syphilitic  epidid}Tnitis  is  not  at  all  an  uncommon  symptom  of  the  disease. 
The  epididymitis  may  be  unilateral  or  bilateral,  and  may  be  well  marked  before 
the  rash  has  even  made  its  appearance.  In  every  case  I  have  seen,  it  has  been  only 
the  caput  major  that  has  been  affected.  The  feel  alone  of  the  epididymis  will 
suggest  s}^hilis  at  once.  The  affected  pole  in  syphilis  feels  uneven,  as  a  bunch  of 
grapes  would  feel  through  a  soft  bag.  In  the  other  infections  which  cause  epididy- 
mitis, the  organ  is  evenly  enlarged,  and  feels  more  or  less  smooth  and  hard  on  the 
.surface.  I  had  one  case  in  which  the  epididjTiiis  became  adherent  to  skin,  broke 
through,  and  produced  a  condition  to  which  the  name  of  hernia  testis  is  sometimes 
given.  In  the  late  stages  of  the  disease,  the  commonest  lesion  is  a  gumma  of  the 
testis,  but  occasionally  a  ginnma  may  be  limited  to  the  epididymis,  in  which  case 
the  caput  minor,  or  body,  is  the  portion  most  frequent)}'  affected.  A  short  time 
ago  I  saw  a  case  of  a  man,  aged  45,  who  never  remembered  having  had  syphilis, 
and  who  came  up  for  advice  for  pain  in  his  "  testicle."  The  caput  minor  was 
enlarged,  hard,  and  slightly  tender,  and  the  whole  of  the  vas  deferens  was  markedly 
thickened.  Had  the  patient  been  younger  and  delicate  looldng,  no  one  would  have 
hesitated  in  diagnosing  the  condition  as  tubercular  epididpuitis. 

However,  the  fact  that  the  condition  cleared  up  under  anti-syphilitic  treatment, 
clearly  showed  that  the  affection  was  syphilitic. 

Hydrocele  may  result  from  any  injury  to  the  epididjauis  or  testis,  and  is  not 
specially  prone  to  occur  in  syphilitic  affections  of  these  organs. 

'  Levy  Bing  et  Durvoux  (191.3),  "  Annales  des  Malad.  Veii6r.,"  i,  242. 

'  Asch  (1911),  "  Zeitschrf.  f.  Urologie,"  v,  504. 

=  Pereschiwldn  (1911),  "  Zeitschrf.  f.  Urologie,"  v,  732. 

'  Dreyer  (1913),  "  Dermat.  Zeitschrf.,"  xx,  477,  591. 


CHAPTER  XVII. 
SYPHILIS  OF  THE  EYES  AND  EARS. 

The  commonest  early  syphilitic  eye  symjitom  is  iritis.  Syphilitic  iritis  does 
not  materially  difier  from  iritis  produced  by  other  causes,  but  it  has  frequently  to 
be  distinguished  from  gonococcal,  or  the  so-called  rheumatic  iritis.  As  a  rule, 
syphilitic  iritis  is  not  so  acute  as  the  gonococcal  form,  but  when  one  is  confronted 
with  a  case  of  iritis,  this  difEerence  is  of  little  value.  It  should  be  remembered  that 
syphilitic  iritis  is  a  symptom  of  early  syphilis.  Gonococcal  iritis  is  more  prone  to 
develop  during  a  recurrent  attack  of  gonorrhoea  than  during  the  initial  infection. 
Gonococcal  iritis  may  arise  mouths  after  the  patient  has  ceased  to  think  of  a 
discharge,  i.e.,  during  the  latent  stage  of  the  disease.  Gonococcal  iritis  is  often 
accompanied  by  gonococcal  rheumatism,  arthritis  and  neuritis.  Gonococcal  iritis 
is  recurrent,  or  even  periodical,  in  one  or  other  eye.  Once  a  patient  has  had  gono- 
coccal iritis,  he  is  always  prone  to  develop  it  again,  although  there  may  be  no 
exacerbation  of  gonococcal  symptoms  elsewhere.  Syphilitic  iritis  may  affect  both  eyes, 
and,  as  a  rule,  they  are  affected  simultaneovisly,  and  it  practically  never  recurs. 

Syphilitic  iritis  disappears  like  magic  under  salvarsau,  while  gonococcal  iritis 
is  improved  only  by  vaccines. 

As  gonococcal  iritis  is  usually  more  acute  than  syphilitic  iritis,  and  is  less  amen- 
able to  treatment,  it  will  follow  that  synechiae  are  more  liable  to  be  found  in  the 
former  than  in  the  latter  infection. 

True  gummata  of  the  iris  and  ciliary  body  may  occur,  but  they  are  very 
rare. 

I  have  seen  one  case  of  syphilitic  dacryo-cystitis,  but  it  is  probable  that  the 
initial  site  of  the  lesion  was  in  the  periosteum  of  the  lachrymal  bone,  and  this 
brought  about  a  narrowing  of  the  nasal  duct  and  sac,  owing  to  the  swelling  which 
had  been  caused.  Choroiditis  is,  on  the  other  hand,  a  common  symptom  of  late 
syphilis.  Almost  invariably  the  condition  is  bilateral,  but  one  eye  may  be  worse 
than  the  other  ;  and,  as  a  rule,  the  symptoms  are  only  subjective,  with  the  results 
that  the  patient  does  not  seek  advice  until  the  condition  is  far  advanced. 


156  THE   BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT    OF   SYPHILIS. 

The  patient  complains  of  seeing  large  floating  specks,  if  asked  to  look  at  parallel 
straight  lines  they  appear  curved,  and  the  patient  may  have  noticed  dark  spots 
in  his  visual  field.  The  vitreous  is  usually  crowded  with  opacities  which  often 
blurr  the  patient's  vision. 

If  the  case  comes  under  observation  during  the  acute  stage,  treatment  will  be 
of  great  benefit ;  but  in  many  cases  the  progress  is  very  insidious,  and  even  the 
most  drastic  form  of  treatment  cannot  stop  it.  Nevertheless,  treatment  must  be 
persisted  in,  as  I  have  had  cases  in  which  the  lesion  appears  to  have  been  brought 
to  a  standstill.  Naturally,  the  scars  left  by  the  disseminated  patches  cannot  be 
altered  by  treatment. 

Interstitial  keratitis  is  a  very  common  symptom  in  congenital  syphilis,  and, 
oddly  enough,  it  may  not  show  itself  until  the  patient  has  become  an  adult.  I 
once  saw  a  case  of  congenital  syphilis,  in  which  the  patient  developed  a  most  acute 
bilateral  interstitial  keratitis,  at  the  age  of  36.  Many  textbooks  state  that  inter- 
stitial keratitis  is  never  seen  in  acquired  syphilis.  I  have  certainl}*  had  three 
cases  under  my  care,  and  in  all  of  them  there  were  other  signs  of  a  recentlj^  acquired 
infection,  and  only  one  eye  was  affected. 

Syphilitic  retinitis  is  usually  associated  with,  and  secondary  to,  choroiditis. 
Isolated  syphilitic  retinitis  is  very  rare.  I  have  seen  only  one  case,  and  that  was 
in  a  patient  who  also  had  a  sj-philitic  myelitis.  In  spite  of  the  most  vigorous 
treatment,  he  sufiered  from  haemorrhages  into  his  vitreous  at  periodical  intervals. 
The  right  eye  was  the  eye  always  affected,  and,  oddly  enough,  in  all  the  cases 
which  have  been  described,  the  lesion  has  been  unilateral.  The  first  haemorrhage 
occurred  a  little  more  than  a  year  after  infection.  As  the  case  is  of  somewhat 
unusual  interest  a  fuller  report  would  not  be  out  of  place. 

Case  18. — August,  1910. — Primary  sore.     Commenced  treatment  at  once. 

February,  1911. — Complete  transverse  myelitis,  which  ended  in  partial  recovery 
after  three  injections  of  salvarsan,  mercurial  inunctions,  and  potassium  iodide, 

October,  1911. — Syphilitic  retinitis,  haemorrhage  into  the  right  eye.  Patient 
then  had  six  intravenous  injections  of  salvarsan  and  mercurial  inunctions. 

April,  1912. — Gumma  on  calf  of  left  leg,  for  which  patient  was  treated  with 
mercurial  injections  and  iodides  internally. 

August,  1912.— Haemorrhage  into  right  eye. 

September,  1912. — Haemorrhage  into  right  eye. 

November,  1912. — Haemorrhage  into  right  eye.  Patient  then  had  seven  intra- 
venous injections  of  salvarsan,  and  one  year's  mercurial  treatment. 

December,  1913.— Haemorrhage  into  right  eye. 

March,  1914.— Haemorrhage  into  right  eye. 


SYPHILIS   OF   THE    EYES    AND    EARS.  157 

November,  1914. — Haemorrhage  into  right  eye.  The  Wasseriuanu  reaction 
has  been  negative,  in  spite  of  the  recurrent  haemorrhages,  for  the  last  two  years. 

Syphilitic  optic  neuritis  is  not  a  very  uncommon  symptom  in  early  syphilis, 
and,  like  most  early  syphilitic  lesions  of  the  eye,  it  is  usually  unilateral.  Optic 
neuritis  in  syphilis  has  come  into  great  prominence  lately,  owing  to  the  fact  that 
blindness  resulted  from  the  use  of  some  of  the  earlier  arsenical  preparations.  There 
is  no  doubt  that  cranial  nerve  lesions  did  increase  in  frequency  when  salvarsan 
first  came  into  use,  but  we  have  since  learnt  that  that  was  due  to  the  fact  that 
salvarsan  was  not  supplemented  by  mercury,  or  to  the  fact  that  not  enough  salvarsan 
had  been  given.  If  a  case  of  optic  neuritis  is  recognised  early,  adequate  treatment 
with  salvarsan  and  mercury  will  quickly  cure  it.  When  the  body  is  infected  with 
syphilis,  the  organisms  invade  every  part  of  it,  and,  as  I  have  shown  in  Chapter  XXIII, 
meningeal  and  nervous  lesions  are  prevented  from  arising,  owing  to  the  antibodies 
circulating  in  the  systemic  part.  Should  the  production  of  these  antibodies  be 
checked — as  occurs  when  salvarsan  is  given,  but  not  in  that  quantity  which  will 
sterilise  the  meninges — it  allows  the  organisms  to  develop  in  the  meninges.  If  they 
develop  around  nerves  which  have  to  pass  through  bony  canals,  it  will  follow  that 
the  pressure  caused  by  the  meningitis  will  inflame  the  nerve,  and  so  lead  to  its 
atrophy. 

Atoxyl  amblyopia  is  due  to  a  direct  degeneration  of  the  optic  nerve  itself,  and 
is  not  secondary  to  a  meningitis.  Salvarsan  does  not  cause  blindness.  I  have 
given  several  thousands  of  injections,  and  I  have  seen  only  one  case  of  optic  neiuitis 
follow  its  use.  This  was  in  the  early  days,  when  it  was  customary  to  give  only  one 
injection.  The  case  improved  under  fmther  administration  of  mercury  and  iodides. 
I  have  seen  three  cases  of  optic  neuritis  in  early  syphilis,  in  patients  who  had  never 
received  any  treatment.  In  one  case  the  eye  became  quite  blind  before  anything 
could  be  done,  and  it  had  subsequently  to  be  removed. 

Late  syphilitic  optic  neuritis  is  usually  bilateral,  and  is  due  to  some  intra- 
cranial mischief. 

Ophthalmoplegia,  or  multiple  ocular  paralyses,  may  be  complete  or  partial, 
and  may  affect  one  or  both  eyes.  If  the  external  muscles  are  affected,  the  term 
Ophthalmoplegia  externa  is  used,  in  contradistinction  to  paralysis  of  all  the  intra- 
ocular muscles — Ophthalnioj)legia  interna. 

Of  all  the  causes  of  the  various  forms  of  ophthalmoplegia,  syphilis  is  probably 
the  most  frequent.  The  paralysis  may  be  either  sudden  or  gradual.  If  sudden, 
and  if  the  patient  is  over  50,  the  paralysis,  which,  as  a  rule,  affects  one  muscle  only, 
is  due  to  an  arteriosclerotic  lesion  of  syphilitic  origin,  and  the  chances  are  that, 
sooner  or  later,  the  patient  will  succumb  to  a  hemiplegia.     If  gradual,  one  muscle 


158  THE   BIOLOGY,    CLINICAL   ASPECT    AND    TREATMENT   OF   SYPHILIS. 

may  be  at  first  affected,  but  in  most  cases,  sooner  or  later,  other  muscles  become 
involved,  and  degenerative  myelitis  generally  ensues. 

Ophthalmoplegia  interna,  although  a  common  symptom  in  degenerative 
myelitis,  and  indeed  it  may  be  the  first  symptom,  may  never  be  followed  by  other 
nervous  manifestations.  In  most  textbooks,  the  reader  will  find  it  stated  that 
pin-point  pupils,  which  react  to  neither  light  nor  to  accommodation,  always  signify 
that  a  widespread  degenerative  lesion  will  ensue  later ;  while  the  occurrence  of 
late  syphilitic  nerve  lesions,  such  as  those  just  mentioned,  following  upon  paralysis 
of  the  external  muscles,  is  barely  mentioned. 

Provided  pin-point  pupils  (the  reflexes  of  which  have  disappeared)  are  the 
only  signs  which  the  patient  has,  the  chances  are  that  further  degenerative  changes 
in  the  central  nervous  system  will  not  set  in.  I  have  been  able  to  collect  eleven 
such  cases.  In  three,  the  patients  had  had  iridoplegia  for  over  30  years,  and  in  seven 
in  which  I  did  a  lumbar  puncture,  the  cerebro-spinal  fluid  was  normal. 

Nearly  every  case  of  degenerative  external  ophthalmoplegia  which  I  have  seen 
has  since  developed  further  degenerative  changes  of  the  nervous  system.  The 
following  case  is  a  typical  example  : — • 

Case  19. — A  patient  contracted  syphilis  in  1904,  and  he  was  treated  for  it  for 
three  years  with  mercury  internally.  In  1910,  patient  complained  of  double  vision. 
He  had  ptosis  of  the  left  eye  and  paralysis  of  the  external  rectus.  Under  treatment, 
the  eye  symptoms  disappeared.  Two  years  later  the  classical  symptoms  of 
degenerative  myelitis  supervened. 

The  following  is  also  an  instructive  case  : — 

Case  20. — Five  years  ago,  patient  had  an  attack  of  double  vision,  which  got  well 
of  its  own  accord.  Three  years  ago  the  double  vision  recurred,  and  the  patient 
had  very  severe  attacks  of  vomiting.  The  patient  was  unaware  that  he  had  ever 
had  syphilis. 

I  thought  the  stomach  pains  were  gastric  crises,  but  the  patient  had  no  other 
symptoms  of  degenerative  myelitis.  Under  the  most  \'igorous  anti-syphilitic  treat- 
ment the  stomach  symptoms  vanished,  but  the  ophthalmoplegia  extended,  until 
the  patient  had  almost  complete  bilateral  ophthalmoplegia  and  ptosis.  The  gastric 
crises  returned,  and  one  by  one  the  other  symptoms  of  degenerative  myelitis  began 

to  reveal  themselves. 

Ears. 

In  earlj'  syphilis,  deafness  is  a  not  infrequent  symptom.  If  the  deafness  is 
bilateral,  and  the  patient  has  a  bad  throat,  it  will  almost  certainly  be  due  to  mucous 
papules  in  the  Eustachian  tubes.  If  unilateral,  the  deafness  will  almost  certainly 
be  due  to  nerve  trouble.      The  nerve  trouble  is  primarily  a  meningitis,  and  is 


SYPHILIS   OF  THE   EYES    AND    EARS.  159 

analogous  to  that  described  in  connection  with  the  optic  nerve.  The  trunk  of 
the  eighth  nerve  may  be  afiected,  or  only  its  cochlear  or  vestibular  branches,  or 
both.  Syphilitic  disease  of  this  cranial  nerve  is  more  often  bilateral  than  is  the 
case  in  any  of  the  other  cranial  nerves. 

If  the  cochlear  branch  alone  is  affected,  the  patient  complains  of  deafness, 
which  may  come  on  suddenly,  but  more  often  gradually.  Its  course  may  be  short, 
or  the  deafness  may  get  worse  so  slowly  that  the  patient's  attention  is  scarcely 
drawn  to  it.  When  the  vestibular  nerve  is  involved,  the  patient  complains  of 
tinnitus,  giddiness  and  vomiting ;  the  vomiting  is  irrespective  of  food,  and  is 
usually  worst  on  getting  up  in  the  morning,  owing  to  the  change  of  posture  causing 
a  disturbance  in  the  semicircular  canals.     In  the  early  stage,  nystagmus  is  present. 

The  following  case  is  typical  of  a  lesion  of  the  trunk  of  the  auditory  nerve  : — 

Case  21. — L.  M.,  female,  aged  35,  came  to  the  hospital  with  psoriasiform  syphilides 
on  her  legs.  Two  years  before,  the  patient  contracted  syphilis,  and  was  treated  for 
eight  weeks  with  inunctions  in  the  General  Hospital,  Yarmouth,  where  she  developed 
double  iritis.  Two  months  after  leaving  hospital,  condylomata  appeared  around 
the  anus  and  between  the  toes.  Since  then  the  patient  had  not  been  treated.  It 
was  noticed  that  she  did  not  seem  to  hear  very  well,  and,  on  inquiry,  she  stated  that 
she  had  been  deaf  in  the  right  ear  for  six  months.  The  deafness  had  come  on 
gradually,  and  was  slowly  getting  worse,  and,  at  the  same  time  as  it  commenced, 
noises  in  the  ear  were  experienced,  and  the  patient  was  much  troubled  with  attacks 
of  giddiness,  which  prevented  her  from  going  out.  The  patient  always  had  the 
feeling  as  if  she  were  going  to  fall  forwards,  and  she  actually  did  so  on  two  occasions. 
The  giddiness  and  vomiting  were  always  worst  on  getting  up  in  the  morning,  and 
the  latter  occurred  during  the  day,  quite  irrespective  of  food.  These  symptoms, 
except  the  giddiness,  were  increasing  in  severity.  When  I  fii'st  saw  her,  she  had 
slight  nystagmus,  which  later  disappeared. 

Examination  of  the  ears  was  kindly  undertaken  for  me  by  Mr.  S.  E.  Scott. 
The  left  external  meatus  showed  old  stenosis,  but  there  was  no  defect  of  hearing 
on  this  side,  and  electrical  reactions  were  normal.  There  was  a  marked  reaction 
to  the  caloric  test  in  one  minute  at  115°  F.,  the  patient  falling  to  the  right.  On 
the  right  side  hearing  was  diminished  ;  no  artificial  Rhomberg's  sign  or  nystagmus 
was  produced  by  syringing  for  three  minutes  with  water  at  118°  F.;  the  electrical 
reactions  of  the  vestibular  nerve  were  sluggish,  but  had  not  quite  disappeared. 
All  pointed  to  a  neuritis  of  the  trunk  of  the  eighth  nerve  on  the  right  side,  most 
probably  of  syphilitic  origin.  This  case  is  instructive,  since  the  patient  had  never 
had  "  606  "  ;  would  not  have  complained  of  her  nerve  condition  had  her  attention 
not  been  drawn  to  it,  and  had  never  connected  it  with  her  disease.     Under  mercurial 


160  THE   BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

injections,  all  s}Tnptoms  referable  to  the  vestibular  branch  cleared  up,  but  the 
deafness  remains  much  about  the  same,  and,  like  so  many  of  these  cases,  is  much 
less  one  day  than  another. 

I  also  saw  a  man  who  became  gradually  deaf  in  one  ear,  four  months  after 
the  appearance  of  the  sore,  and  who  had  had  no  treatment  at  all.  His  deafness 
almost  completely  disappeared  three  months  after  two  intravenous  injections  of 
salvarsan  and  eight  intramuscular  injections  of  grey  oil. 

The  cochlear  branch  is  not  infrequently  implicated  alone — much  more  commonly 
so  than  the  vestibular. 

Apart  from  a  neuritis  of  the  eighth  and  second  cranial  nerves,  of  which  the 
former  is  more  frequent  than  the  latter,  the  other  cranial  nerves  are  involved  in 
the  following  order  of  frequency  :  seventh,  third,  fourth,  fifth  and  sixth.  I  have 
seen  three  cases  of  facial  palsy,  in  which  the  nerve  affection  was  almost  the  first 
symptom  of  the  generalisation  of  the  virus.  All  recovered  completely  after 
salvarsan  and  mercury. 

When  a  neuritis  of  a  cranial  nerve  sets  in  after  "  606,"  in  96  per  cent,  of  cases 
it  does  so  within  the  first  four  months  ;  the  cases  are  almost  invariably  in  the 
generalisation  stage,  the  Wassermann  reaction  is  generally  negative — that  is  to 
say,  if  the  lesion  has  occurred  after  treatment,  when  its  onset  is  usually  later  in  the 
disease — and  the  patients  have  usually  had  only  one  injection.  This  marked 
similarity,  as  regards  onset  and  occurrence,  finds  its  explanation,  if  we  consider 
the  frequency  of  neuritis  in  sj'philis  before  the  days  of  "  606." 

So  slight,  so  gx-adual  in  onset  and  progression,  may  sjTiiptoms  of  a  neuritis 
of  the  cranial  nerves  be,  that  the  patient  does  not  connect  them  with  his  disease, 
and  consequently  does  not  draw  his  doctor's  attention  to  them.  By  astute 
observers  they  have  been  noticed  and  described,  but,  beyond  this,  cranial  nerve 
lesions  in  syphilis  have  not  received  the  recognition  due  to  them. 

Their  occurrence  after  "  606  "  made  syphilologists  examine  their  casejs  more 
thoroughly  before  treatment,  with  the  astonishing  result  that  the  frequency  of  such 
lesions  was  nearly  as  great  as  that  of  those  reported  to  be  due  to  salvarsan.  They 
noticed  further  that  these  nerve  afl'ections  were  not  uncommon  early  in  the 
generalisation  stage,  setting  in  within  a  year  of  infection,  that  they  were  more  often 
unilateral  than  bilateral,  and  were  just  as  common  in  patients  who  had  not  had 
any  mercury  as  in  those  who  had,  although  it  has  more  than  once  been  stated 
that  they  were  more  common  after  the  use  of  soluble  preparations  than  they  were 
after  the  insoluble  salts  of  mercury.  These  facts  show  that  nerve  lesions  are 
syphilitic  manifestations,  and  that  their  occurrence  after  "  606  "  signifies  inadequate 
treatment,  and  that  they  are,  in  short,  neuro-recurrences. 


SYPHILIS   OF  THE  EYES  AND   EARS.  161 

While  on  the  subject  of  syphilis  of  the  cranial  nerves,  I  should  like  to  mention 
an  ear  symptom  which  commonly  occurs  when  the  facial  nerve  is  affected.  The 
patient  complains  of  odd  noises  in  his  head,  on  the  side  affected,  and  he  likens  them 
to  vibrations.  This  is  due  to  paresis  of  the  nerve  supplying  the  stapedius  muscle. 
I  have  had  four  cases  of  unilateral  facial  paralysis.  All  set  in  suddenly,  from  six 
to  twelve  weeks  after  the  sore  was  first  noticed,  and  in  two  the  stapedial  nerve 
was  affected.  The  vibrations  complained  of  were  not  incessant,  but  came  on  in 
attacks,  which  gi-adually  lessened  as  the  patient  got  better,  but  in  both  cases  the 
patients  had  reminders,  even  two  years  later. 

Late  syphilitic  deafness  is  usually  bilateral,  although  one  ear  may  be  affected 
before  the  other.  The  deafness  is  usually  progressive,  and,  in  my  experience, 
treatment  usually  makes  it  worse. 

Meniere's  symptom  complex — deafness,  giddiness,  tinnitus  and  vomiting — 
although  an  uncommon  sequence  of  syphilis,  is  met  with  occasionally  as  a  late 
syphilitic  manifestation ;  but  opinions  differ  as  to  whether  treatment  improves  the 
condition  or  not,  as  it  is  by  no  means  easy  to  be  sure  whether  syphilis  is  the 
cause,  even  if  the  patient  has  had  the  disease. 


l2 


CHAPTER  XVIII. 
SYPHILIS  OF  THE  MOUTH  AND  THROAT. 

A  chancre  may  occur  anywhere,  but  there  is  one  type  of  chancre  to  which 
special  reference  should  be  made,  because  of  the  way  in  which  it  simulates  a  large 
spored  ringworm  lesion.  It  is  called  the  hypertrophic  chancre,  and  it  may  be 
situated  at  the  corners  of  the  mouth  or  on  the  lips,  where  the  skin  and  mucous 
membrane  join.  The  differential  diagnosis  is  simple,  if  it  always  be  remembered 
that  chancres  in  the  oral  region  are  always  accompanied  by  very  marked  enlarge- 
ment of  the  lymphatic  glands. 

The  so-called  mucous  patches  are  nothing  more  nor  less  than  syphilitic  papules. 
A  patient  who  has  had  syphilis,  especially  if  he  has  been  treated  with  mercury 
internally,  is  very  liable  to  develop  attacks  of  Herpes  oris  and  aphthous  ulcers.  Fear 
of  a  recurrence  of  symptoms  usually  accompanies  each  outbreak,  and  as  these  ulcers 
are  so  frequently  confounded  with  mucous  papules,  it  would  be  well  to  draw  atten- 
tion to  their  differentiation.  Mucous  papules,  like  all  syphilitic  lesions,  are  non- 
inflammatory— that  is  to  say,  a  mucous  papule  is  well  circumscribed,  and  has  no 
inflammatory  ring  surrounding  it.  A  mucous  papule  is  white  and  raised  above  the 
surface.  Herpes  starts  as  a  crop  of  vesicles,  which  quickly  become  small  ulcers. 
Often  the  vesicular  stage  is  not  observed.  Each  lesion  has  a  yellow  base  which  is 
depressed  beneath  the  surface,  and  each  lesion  is  surrounded  by  a  marked  inflam- 
matory ring.  An  aphthous  ulcer  has  exactly  the  same  appearance  as  the  ulcerative 
stage  of  the  herpetic  lesion,  and  it  is  highly  probable  that  the  two  terms  are  only 
different  names  for  the  same  condition. 

The  ulcers  are  painful ;  the  mucous  papules  are  painless.  The  former  may 
appear  in  24  hours  ;  the  latter  do  not  appear  for  several  days.  Therefore,  there 
should  never  be  any  difficulty  in  differentiating  between  the  two  conditions. 

A  very  common  site  for  an  aphthous  ulcer  is  the  space  posterior  to  the  last 
tooth  on  either  side  of  the  lower  jaw.  When  this  heals,  the  surface  has  a  white 
irregular  appearance,  which  suggests  leucoplakia.  Smiilar  white  patches  are 
frequently  seen  in  the  cheeks,  and  indeed  on  any  part  of  the  mucous  membrane 
in  the  mouth,  in  patients  who  have  taken  mercury  internally. 


■     SYPHILIS    OF   THE    MOUTH    AND    THROAT.  163 

Leucoplakia  is  regarded  by  many  as  being  pathognomonic  of  syphilis.  Leuco- 
plakia  is  merely  an  attempt  of  the  mucous  membrane  to  form  a  stratum  corneum, 
as  it  will  always  try  to  do,  whatever  be  the  nature  of  the  irritant. 

Leucoplakia  of  the  tongue  is  common  in  syphilis,  and  is  usually  met  with  in 
those  cases  which  have  received  no  treatment,  and  in  those  which  have  been  treated 
with  mercury  internally. 

Smoking  will  cause  leucoplakia  in  a  non-syphOitic  subject,  .so  will  psoriasis, 
Lichen  planus,  etc. 

Leucoplakia  may  be  followed  later  by  carcinoma,  but  it  is  not  the  leucoplakia 
which  predisposes  the  organ  to  imdergo  the  cancerous  change  ;  it  is  merely  the 
persistence  of  the  irritant  which  primarily  led  to  the  production  of  the  leucoplakia. 
Leucoplakia  is  a  manifestation  of  the  protective  mechanism  of  the  cells,  against  the 
agent  which  is  irritating  them. 

If  the  epithelial  cells  persist  indefinitely  in  undergoing  changes  of  a  protective 
nature,  the  cells  will  ultimately  become  parasitic  upon  the  host  which  gave  rise 
to  them — i.e.,  they  will  become  cancerous,  but  that  does  not  mean  to  say  that  the 
leucoplakia  is  the  cause  of  the  cancer,  an  opinion  which  is  very  widely  held. 

A  leucoplakic  tongue  may  remain  as  innocent  as  a  normal  tongue,  or  may 
quickly  become  cancerous.  Which  of  these  results  will  supervene,  will  depend,  not 
upon  the  degree  of  the  leucoplakia,  but  upon  the  nature  of  the  irritant  which  gave 
rise  to  the  leucoplakia. 

The  changes  which  the  tongue  undergoes  in  syphilis  are  both  interesting  and 
important,  owing  to  the  frequency  with  which  the}'  end  in  cancer. 

The  changes  about  to  be  described,  broadly  speaking,  are  only  to  be  seen  iu 
those  cases  of  syphilis  which  are  not  treated  at  all,  and  in  those  which  are  treated 
with  mercury  internally. 

Absence  of  treatment  does  not  prevent  the  tongue  from  becoming  infected 
directly  with  the  organisms  of  syphilis.  Oral  administration  of  mercury  frequently 
causes  indigestion,  and  indigestion  is  liable  to  cause  inflammation  in  any  part  of  the 
mouth,  especially  in  the  tongue.  Other  factors  also  come  into  play,  namely, 
bad  teeth,  smoking,  tobacco  chewing,  alcohol,  etc.,  all  these  are  liable  to 
increase  or  to  keep  up  any  inflammatory  changes  which  have  been  initiated  by 
syphilis. 

The  first  change  to  be  noted  is  a  swelling  of  the  base  of  the  tongue,  and  this 
frequently  leads  to  the  patient  seeing  the  circumvallate  papillae,  for  the  first  time 
in  his  life.  After  recovering  from  the  shock,  he  runs  up  to  his  doctor  for  advice  as 
to  what  to  do  for  the  sores  or  spots  at  the  back  of  his  tongue.  This  swelling  soon 
extends  to  the  anterior  part  of  the  tongue,  when  the  tongue  appears  to  be  too  big 


164  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   SYPHILIS. 

for  the  mouth,  and  its  edges  clearly  show  the  irregularity  caused  by  the  pressure 
of  the  teeth. 

Swelling  indicates  parenchymatous  inflammation.  If  the  inflammation  persists, 
fibrous  tissue  formation  is  the  result.  Fibrous  tissue  contracts,  and  hence  the 
tongue  becomes  smaller  than  it  normally  was. 

Fibrous  tissue  contraction  indicates  loss  of  blood  supply  to  surface,  hence  the 
papillae  vanish,  the  dorsum  of  the  tongue  takes  on  a  smooth,  glazed,  shiny  appear- 
ance, and  then  the  epithelium  begins  to  protect  itself  by  forming  horny  tissue. 

The  inflammation  may  not  be  evenly  marked  all  over  the  tongue.  In  some 
places  it  may  be  worse  than  in  others,  hence  the  tongue  may  be  atrophic  in  some 
parts  and  hypertrophic  in  others.  This  irregularity  leads  to  fissure  formation, 
and  as  fissures  occur  where  the  fibrous  tissue  is  densest  and  the  blood  supply  is 
poorest,  it  can  be  easily  understood  how  readily  ulceration,  and  even  cancer  may 
arise.  AVarts  are  very  liable  to  occur  in  the  atrophic  areas,  and  the  risk  of  these 
becoming  malignant  is  great.  Cauterisation  will  stimulate  their  malignant  ten- 
dencies, therefore,  on  no  condition  whatever  should  caustics  ever  be  applied  to  a 
tongue,  or  indeed  to  any  other  mucous  membrane.  The  warts  should  be  locally 
excised.  There  is  no  necessity  to  remove  half  the  tongue,  as,  in  these  atrophic 
tongues  which  became  malignant,  the  process  is  so  slow  and  localised,  and  it 
practically  never  gives  rise  to  a  metastasis. 

When  an  ulcer  becomes  malignant,  it  is  a  different  question.  Removal  of  half 
or  the  whole  of  the  tongue  and  the  lymphatic  glands  is  usually  the  most  expedient 
course  to  adopt. 

Tonsil. 

A  primary  sore  may  have  its  seat  in  the  tonsil,  when  it  invariably  gives  rise  to 
a  difficulty  in  diagnosis. 

A  primary  sore  has  to  be  distinguished  from  a  well-marked  case  of  follicular 
tonsillitis,  a  gumma  of  the  tonsil,  and  from  Vincent's  angina.  Over  and  over 
again,  these  four  conditions  have  been  confused  with  one  another,  although  the 
differential  diagnosis  between  them  should  never  present  any  difficvdties. 

A  chancre  is  often  a  superficial  lesion,  circumscribed,  and  not  surrounded  by  an 
inflammatory  area.  On  the  other  hand,  a  chancre,  owing  to  secondary  infection, 
is  more  often  a  deep  ulcer,  and  then  the  area  surrounding  it  is  naturally  very 
much  inflamed.  Whether  the  chancre  of  the  tonsil  is  secondarily  infected  or  not, 
the  enlargement  of  the  lymphatic  glands  is  always  very  much  more  marked  than 
is  the  case  with  follicular  tonsillitis.  Follicular  tonsillitis  is  very  painful,  a  chancre 
of  the  tonsil  is  not.     Follicular  tonsillitis  is  ushered  in  with  fever,  rigor,  etc.,  and, 


SYPHILIS  OF  THE  MOUTH  AND  THROAT.  165 

throughout  its  course,  the  patieut  feels  very  ill,  and  almost  invariably  small  areas 
of  folliculitis  will  be  observed  on  the  opposite  tonsil.  A  chancre  of  the  tonsil  begins 
insidiously  :  the  patient  does  not  feel  ill,  and  the  act  of  swallowing  usually  causes 
nothing  more  than  a  mere  feeling  of  slight  discomfort. 

A  gumma  causes  more  destruction  of  tissue,  for  its  size,  than  a  chancre,  and  it 
is  unaccompanied  by  an  enlargement  of  the  lymphatic  glands. 

Vincent's  angina  is  usually  mistaken  for  a  chancre,  or  more  often  for  a  gumma. 
The  course  of  Vincent's  angina  should  suffice  to  distinguish  it  from  any  other 
condition.  The  patient  suddenly  feels  very  ill,  the  temperature  shoots  up,  and  the 
patient  may  have  a  rigor  ;  in  two  or  three  days  there  is  a  deep  ulcer  in  the  tonsil^ 
extreme  pain  on  swallowing,  and  only  a  very  slight  enlargement  of  one  or  two 
lymphatic  glands.  The  rapidity  with  which  the  ulcer  develops  is  the  pathognomonic 
sign  of  Vincent's  angina,  and  a  point  which  absolutely  excludes  syphilis,  is  an 
affection  of  the  opposite  tonsil. 

A  film  made  from  a  case  of  Vincent's  angina  will  also  quickly  settle  the  diagnosis, 
since  the  condition  is  caused  by  two  organisms  which  live  in  symbiosis,  namely 
an  irregularly  coiled  Gram  negative  spirochaeta  and  a  Gram  positive  fusiform 
bacillus. 

Syphilitic  periostitis  and  its  sequelae  are  so  absolutely  pathognomonic  of 
syphilis,  that  only  a  passing  word  is  necessary. 

Syphilitic  periostitis  of  the  hard  palate  often  leads  to  ulceration  and  perfora- 
tion of  the  bone,  and  it  is  not  at  all  an  uncommon  symptom  in  both  acquired  and 
congenital  syphilis. 

In  acquired  syphilis,  so  far  as  the  nose  is  concerned,  a  perichondritis  is  more 
common  than  a  periostitis,  and  this  almost  invariably  results  in  a  perforation  of  the 
nasal  septum. 


CHAPTER  XIX. 
SYPHILIS  OF  THE  BRONCHI  AND  LUNGS. 

A  syphilitic  bronchial  catarrh  is  not  very  uncommon,  but  it  is  more  frequently 
seen  as  a  recurrent  syphilitic  manifestation  than  as  an  early  symptom  of  the  disease. 
The  chronic  ulcerative  syphilitic  bronchitis  may  occur  alone,  but  it  is  more  often 
associated  with  a  similar  condition  in  the  trachea,  larynx  or  pharynx. 

This  late  syphilitic  bronchitis,  as  a  rule,  affects  only  one  or  other  of  the  chief 
bronchi,  and  the  most  usual  situation  for  the  ulcers  is  in  the  neighbourhood  of  the 
bifurcation. 

The  ulceration  causes  a  thickening  and  raising  up  of  the  mucous  membrane, 
and  these  two  changes  together  give  rise  to  violent  fits  of  coughing,  and,  at  the  end 
of  a  fit,  there  may  be  a  haemorrhage. 

No  signs  are  to  be  found  in  the  lungs.  An  X-ray  examination  of  the  chest 
gives  no  clue  to  the  condition,  and  the  diagnosis  is  rendered  extraordinarily  difficult. 
I  have  seen  only  one  case,  and  the  symptoms  were  coughing  and  haemorrhage.  The 
patient  first  of  all  comjjlained  of  a  peculiar  feeling  in  the  throat,  which  led  to  slight 
attacks  of  coughing.  Later,  these  attacks  became  more  frequent  and  lasted  longer, 
until  ultimately  every  attack  resulted  in  a  severe  haemorrhage. 

Repeatedly  the  patient  would  experience  difficulties  in  breathing,  and  his 
complexion  would  assume  the  colour  associated  with  venous  congestion.  , 

Anti-syphilitic  treatment  stopped  the  symptoms  at  once,  but,  in  the  course 
of  two  years,  the  patient  had  three  very  severe  relapses,  which  were  checked  imme- 
diately by  further  treatment.  Ultimately  the  ulcers  doubtless  scarred  over,  as  the 
patient  has  been  free  of  any  trouble  for  over  two  years.  Considering  the  severity 
of  the  haemorrhage  in  this  case,  the  ulcers  must  have  developed  backwards,  and 
eroded  a  small  bronchial  vessel. 

Cases  have  been  reported  in  which  the  scarring  resulting  from  the  healed  ulcers 
has  given  rise  to  stenosis.  Purulent  mediastinitis  and  lobar  pneumonia  may  also 
be  the  end  of  a  case  of  gummatous  bronchitis.  Symptoms  of  an  ulcerative 
bronchitis  may  be  produced   by  a  syphilitic    process,  starting  in   the  bronchial 


SYPHILIS    OF   THE   BRONCHI    AND   LUNGS.  167 

lymphatic  glands,  which  become  adherent  to  the  bronchi,  and  may  even  ulcerate 
through. 

Lungs. 

Syphilitic  aii'ection  of  the  lungs  is,  in  my  opinion,  commoner  than  is  thought 
to  be  the  case,  but  unfortunately  its  diagnosis  is  fraught  with  great  difficulties, 
owing  to  the  lesions  being  well  nigh  indistinguishable  from  those  produced  by 
tuberculosis.  Therefore,  no  trustworthy  evidence  as  to  its  frequency  is  to  be 
obtained.  There  is  still  a  great  difference  of  opinion  as  to  the  influence  of  s3-philis 
on  the  incidence  of  tuberculosis  of  the  lungs,  and  vice  versa. 

I  think  there  can  be  no  doubt  that  individuals  whose  resistance  against  tuber- 
culosis is  lowered  are  more  prone  to  develop  this  disease,  if  they  also  suffer  from 
syphilis.  In  support  of  this  view  may  be  mentioned  the  not  infrequent  occurrence 
of  tuberculous  adenopathy  in  congenital  syphilitics,  and  the  very  high  incidence 
of  pulmonar}- tubercidosis  in  the  black  races,  in  those  individuals  who  have  syphilis. 
If  a  patient  has  tuberculosis  and  S3'philis,  the  latter  disease  aggravates  the  former, 
but  the  former  appears  to  have  no  influence  upon  the  course  run  by  the  latter. 

Treatment  of  syphilis  has  its  usual  effect  on  the  disease,  whether  tubercle  is 
present  or  not,  but  it  is  seldom  that  the  tuberculosis  is  much  influenced  by  it,  indeed 
mercury  and  iodide  may  make  the  tuberculosis  worse.  From  this  it  would  appear 
that  there  is  little  ground  for  assuming  that  a  lesion  could  be  caused  by  an  association 
of  tubercle  and  syphilis. 

In  recent  years,  one  has  not  infrequently  heard  the  diagnosis  made,  that  a 
certain  orchitis  or  an  arthritis  is  due  to  a  combination  of  syphilis  and  tubercle. 
Such  a  diagnosis  shows  that  the  observer  does  not  know  whether  it  is  tubercle  or 
syphilis,  and,  to  save  himself  from  making  a  mistake,  he  says  the  lesion  is  due  to  a 
combination  of  the  two  diseases. 

When  the  differential  diagnosis  of  a  lesion  between  tubercle  or  s3-philis  arises, 
it  can  be  taken  for  certain  that  the  lesion  is  due  to  either  one,  but  never  to  a  com- 
bination of  both. 

As  the  changes  produced  in  the  lung  by  tubercle  and  syphilis  are  much  alike, 
it  is  often  impossible  to  differentiate  between  them. 

Broadly  speaking,  the  area  affected  by  syphilis  is  greater  than  that  affected  by 
tubercle,  and  the  sjTnptoms  produced  are  relatively  greater  in  tubercle  than  in 
syphilis. 

Syphilis  affects  the  middle  and  lower  lobes  more  often  than  the  upper  lobe  ; 
but  a  true  syphilitic  apical  lesion  may  be  met  with.  So  far  I  have  had  three  cases 
under  my  care.     One  of  these  used  to  get  periodically  very  severe    attacks  of 


168  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

haemoptysis,  but  tuberculosis  could  easily  be  excluded,  because  the  patient  always 
felt  ^yell,  he  never  looked  ill,  he  never  lost  weight,  and  anti-syphilitic  treatment 
benefited  him.  Syphilitic  lesions  are  more  bronchiectatic  than  tubercidar  ones, 
hence  one  of  the  best  diagnostic  means  is  the  X-rays.  Salvarsan  has  a  rapid  action 
upon  sj^hilitic  lung  lesions,  therefore,  if  there  is  any  difference  in  the  X-ray  picture 
before  and  after  treatment,  one  can  be  practically  certain  that  the  condition  was 
sj^ohilitic. 

As  is  well  known,  pulmonary  tuberculosis  is  frequently  preceded  by  pleurisy. 
This  is  not  the  case  in  syphilis — not  that  syphilis  does  not  affect  the  pleura,  but, 
in  practically  all  cases  of  syphilitic  pleuritis,  the  pleuritis  is  only  part  of  a  wide- 
spread pulmonary  affection. 

The  following  is  a  good  case  of  pulmonary  sj'philis  which  I  had  under  my  care  : — 
Case  22. — Patient,  a  man  now  aged  47,  contracted  syphilis  10  years  ago,  and, 
10  months  ago,  began  to  be  troubled  with  a  cough.  The  cough  was  dry  and  hard  ; 
it  was  not  worse  at  any  one  time  of  the  day,  and  there  was  no  expectoration. 
Friction  sounds  were  discernible  almost  all  over  the  lung  area,  and  those  who 
examined  him,  said  that  there  were  changes  in  the  lung  which  were  undoubtedly 
due  to  tubercle.     The  patient  went  away,  did  what  he  was  told,  and  became  much 

worse. 

Seven  mouths  later  I  saw  him.     He  looked  as  if  he  had  fever,  but  was  not 

emaciated,  and  I  learned  that  he  had  lost  no  weight ;  he  had  never  had  an  haemo- 
ptysis, and  there  was  no  expectoration.  Friction  sounds  could  be  heard  over  both 
lungs,  and  on  the  left  side  were  signs  of  both  thickened  pleura  and  patches  of 
consolidation.  There  was  no  family  history  of  tubercle  ;  the  patient  had  spent 
his  life  in  British  East  Africa,  where  tubercle  amongst  the  white  population  is 
almost  unknown.  He  looked  too  well  to  have  such  widespread  tuberculous  lung 
symptoms,  and,  as  there  had  never  been  any  expectoration  or  loss  of  weight,  I 
considered  the  trouble  must  be  due  to  syphilis. 

After  the  first  injection  of  neo-salvarsan,  the  cough  vanished,  and,  by  the  time 
the  fourth  had  been  given,  practically  all  the  physical  signs  had  disappeared,  except 
for  some  impaired  resonance  over  left  lung  behind. 


CHAPTER  XX. 
SYPHILIS    OF    THE    BONES   AND    JOINTS. 

In  discussing  syphilis  of  the  bones,  lesions  of  the  periosteum  are,  of  course, 
included,  and  for  the  sake  of  making  the  description  of  the  subject  easier,  the 
lesions  of  the  periosteum  vrill  not  be,  as  they  usually  are,  considered  separately 
from  those  of  the  bones. 

Although  perhaps  as  much  attention  has  been  paid  to  syphilis  of  the  bones 
as  to  that  of  any  of  the  other  organs,  none  of  us  knows  for  certain  whether,  in  the 
majority  of  the  cases  which  we  call  periostitis,  the  disease  really  started  in  the 
periosteum,  or  in  the  bone  itself.  Many  observers  hold  to-day  that  there  is  no 
such  thing  as  primary  syphilitic  periostitis.  Others  are  of  the  opinion  that 
syphilitic  disease  of  the  bones  always  begins  in  the  periosteum,  and  that  those 
severe  cases  of  osteitis  and  osteomyelitis,  which  were  much  more  often  seen  years 
ago  than  they  are  now,  were  due  to  the  mercury  which  had  been  prescribed  for  the 
disease. 

There  is  no  doubt  at  all  that  the  injudicious  use  of  mercury,  which  was  practised 
only  a  comparative^  short  time  back,  was  partly  responsible  for  a  large  amount 
of  bone  trouble.  This  planted  the  seeds  of  suspicion,  which  have  blossomed  forth 
into  that  mistrust  of  mercury  which  is  possessed  by  so  many  lay  people  to-day. 

The  view  that  was,  and  is  still  held,  is  that  mercury  caused  bone  trouble  by 
collecting  tn  Joco;  but  animal  experiments,  and  the  fact  that  those  who  work  in 
quicksilver  mines,  are  no  more  prone  to  bone  diseases  than  those  who  follow  other 
trades,  all  militate  against  current  opinion.  The  fact  that  the  patient  has  syphilis 
is  an  important  factor.  Secondary  anaemia  in  syphilis  is  common  ;  mercury 
often  aggravates  this  secondary  anaemia.  Fatty  degeneration  is  a  frequent  result 
of  syphilitic  inflammation.  Fatty  degeneration  causes  a  diminution  of  calcium, 
so  does  the  prolonged  and  injudicious  use  of  mercury.  Therefore,  although  one 
may  still  hold  the  view  that  mercury  was  the  cause  of  many  of  the  fine  specimens 
of  bone  diseases  which  adorn  our  museums,  it  must  be  said  that  it  was  not  entirely 
responsible. 


170  THE   BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

The  periosteum  is  continuous  with  the  interstitial  tissue  which  interlaces  the 
parenchyma  of  the  bone.  The  organism  of  syphilis  develops  in  the  interstitial 
tissue,  and  not  in  the  parenchyma.  Therefore,  it  will  at  once  be  seen  that  syphilitic 
osteitis  cannot  be  separated  from  syphilitic  periostitis.  It  may  be  said,  with  a 
great  degree  of  certainty,  that  a  syphilitic  periostitis  cannot  occur  without  an 
osteitis,  and  vice  versa. 

Therefore,  instead  of  making  two  divisions,  it  appears  to  me  to  be  wiser  to 
talk  about  syphilitic  osteoperiostitis,  as  the  signs  and  symptoms  produced  by  the  two 
are  identical. 

Syphilitic  Osteoperiostitis. 

Any  bone  in  the  body  may  be  affected.  Of  the  long  bones,  the  tibia,  humerus, 
ribs,  and  clavicle  are  the  most  commonly  involved,  and  of  the  flat  bones  the  nasal, 
frontal  and  parietal. 

There  is  a  great  difference  in  the  course  run  between  syphilitic  osteoperiostitis 
of  the  flat,  and  of  the  long  bones. 

In  the  case  of  the  long  bones,  the  process  is  generally  dry  throughout,  i.e., 
there  is  no  liquefaction  of  tissue,  and  no  pus  formation.  Therefore  the  process 
is  one  which  can  scarcely  be  called  gummatous.  The  skin  over  the  bones  often  is 
not  even  inflamed.  Such  a  process  invariably  ends  in  new  bone  formation,  and 
this  corresponds  in  size  with  the  area  affected.  The  new  bone  formed  is  very  hard, 
may  be  eburnated,  usually  smooth  on  the  surface,  always  sharply  circumscribed, 
and  is,  as  a  rule,  surrounded  by  a  groove.  Should  the  case  be  one  of  true  gummatous 
osteoperiostitis,  there  will  be  destruction  of  bone,  of  the  nature  of  a  rarifying  osteitis, 
in  the  region  affected  ,  but  around,  and  in  between  the  gummatous  areas,  osteo- 
phytic  growths  are  always  to  be  found. 

In  gummatous  osteoperiostitis,  the  overlying  tissues  are  inflamed,  oedematous 
and  there  is  often  marked  ulceration  of  the  skin.  Many  of  the  ulcers  are  fistulae, 
which  reach  down  to  the  bone.  Osteoperiostitis  of  the  flat  bones  is,  aln\ost  in- 
variably, of  a  gummatous  nature.  The  patient  frequentl}^  seeks  advice  for  swellings 
of  the  forehead  and  scalp.  These  swellings  may  or  may  not  be  inflamed  ;  they 
usiially  fluctuate,  and  the  diagnosis  of  lipomata,  sebaceous  cysts,  or  cold  abscesses, 
is  usually  made. 

On  incising  them,  extremely  little  pus  comes  away,  and  as  such  a  procedure 
may  allow  coccogenic  bacteria  to  gain  entrance,  an  acute  osteomyelitis  of  the  diploe 
may  result,  therefore,  on  no  condition  whatever,  should  an  exploratory  incision  be 
made.  Only  quite  recently  there  was  a  death  at  the  Lock  Hospital  from  a  pyogenic 
infection,  which  had  supervened  upon  a  gummatous  osteomyelitis  of  the  diploe. 
The  dura  mater  was  covered  with  pus. 


SYPHILIS    OF   THE    BONES    AND   JOINTS.  171 

There  is  always  a  destruction  of  bone  in  these  cases,  and  it  may  remain  limited 
to  the  outer  plate,  or  it  may  reach  right  through  to  the  dura  mater,  which  practically 
always  remains  intact. 

In  by  far  the  greater  percentage  of  cases,  the  osteoperiostitis  affects  the  externa 
plate  and  the  pericranium,  but  neither  the  internal  plate  nor  the  periosteum. 

An  hypertrophy  of  bone,  and  the  formation  of  osteophytic  growths,  is  prac- 
tically never  seen  in  the  skull  bone  lesions.  The  reason  why  osteoperiostitis  of  the 
long  bones  runs  a  different  course  from  that  of  the  flat  bones  depends  upon  blood 
supply. 

The  arterial  blood  supply  to  the  scalp  is  extraordinarily  rich,  hence  gumma  forma- 
tion and  the  spread  of  the  process  is  therefore  favourable,  and,  finally,  arterial  blood 
can  cause  bone  atrophy.  Inflammation  of  the  extremities,  where  the  arterial  blood 
supply  is  not  so  good,  favours  venous  congestion,  and  venous  congestion  is  a  potent 
factor  in  the  causation  of  bone  hypertrophy.  Syphilitic  osteoperiostitis,  such  as  that 
just  described,  may  occur  as  early  as  a  few  months  after  infection,  or  may  not  occur 
for  several  years.  Early  gummatous  osteoperiostitis  affects  the  fiat  bones  more 
frequently  than  the  long  bones.  In  the  case  of  the  nasal  bones,  it  is  highly  probable 
that  the  initial  trouble  arises  in  the  submucous  tissue,  and  involves  the  periosteum 
and  bone  later,  since  it  practically  never  happens  that  the  skin  surface  of  the  bones, 
or  the  skin  itself,  becomes  attacked. 

During  the  stage  of  the  generalisation  of  the  virus,  there  may  be  an  inflamma- 
tion of  the  periosteum  of  the  long  bones,  and  this  often  causes  severe  pain  ;  but, 
as  a  rule,  nothing  is  to  be  seen  or  felt.  Even  in  the  later  stages  of  syphilis,  when 
no  swelling  can  be  seen,  a  commencing  osteoperiostitis  may  be  accompanied  with 
such  violent  pain  as  to  lead  one,  if  in  a  hurry,  to  make  a  diagnosis  of  neuritis. 
Local  tenderness  on  pressure  and  the  distribution  of  the  pain  soon  suggest  the 
seat  of  the  trouble.  However  severe  bone  pain  may  be,  it  very  quickly  responds 
to  treatment,  while  the  pain  of  neuritis  is  often  temporarily  aggravated. 

Another  pitfall  for  the  unwary  is  the  diagnosis  of  a  syphilitic  osteoperiostitis 
as  a  sarcoma.  Quite  recently  I  have  had  three  such  cases.  On  two,  an  exploratory 
incision  was  made,  and  the  third  was  advised  to  have  an  operation,  but  refused. 
The  mistake  has  even  lead  to  the  removal  of  limbs. 

Syphilis  does  not  only  affect  the  bone  and  periosteum,  it  may  also  affect  the 
medulla.  As  a  rule,  from  a  clinical  examination  only,  'a  syphilitic  osteomyelitis 
cannot  be  diagnosed  from  a  syphilitic  osteoperiostitis.  In  a  large  number  of 
cases,  when  one  is  in  a  position  to  examine  the  bone,  it  is  found  in  a  condition 
of  panosteitis,  i.e.,  the  periosteum,  the  bone  itself,  and  the  medulla  are  all 
affected. 


172  THE    BIOLOGY,    CLINICAL   ASPECT    AND   TREATMENT   OF   SYPHILIS. 

Some  of  those  cases  with  chronic  oedema,  ulceration,  and  fistula  formation  of 
one  leg,  are  really  cases  of  syphilitic  osteomyelitis,  or  better  to  say,  panosteitis. 

Only  an  X-ray  photograph  can  indicate,  during  life,  whether  the  medulla 
is  involved  or  not.  If  the  medulla  is  affected,  the  inflammation  is  of  the  gummatous 
type,  with  the  result  that  the  medullary  surface  of  the  true  bone  shows  marked 
signs  of  rarefying  osteitis.  The  abscess  formation,  so  common  in  tubercle,  is  not 
met  with  in  syphilis.  One  of  the  best  ways  of  distinguishing  a  syphilitic 
osteomyelitis  from  a  tubercular  one,  is  to  remember  that  lipoid  or  fatty  degenera- 
tion is  a  typical  feature  of  a  syphilitic  process,  when  there  is  destruction  of  tissue. 
Consequently,  a  fresh  or  a  well  prepared  specunen  of  osteomyelitis  looks  yellow  and 
full  of  fat,  while  a  tubercular  osteomyelitis  has  a  white  or  more  waxy  appearance. 

Cases  of  spontaneous  fracture  have  been  recorded,  following  syphilitic  osteo- 
myelitis. 

Syphilitic  bone  lesions  show  rather  clearly  the  influence  which  irritation  or 
continued  trauma  has  upon  their  origin. 

The  clavicles  are  most  prone  to  develop  osteoperiostitis  at  the  place  where  the 
braces  touch  the  skin.  Shoemakers  are  liable  to  osteoperiostitis  of  the  sternum, 
and  it  is  highly  probable  that  the  reason  why  the  tibiae  are  so  commonly  affected, 
is  because  of  their  prominent  position,  and  because  of  the  fact  that  the  anterior 
surface  is  not  guarded  by  muscle. 

Syphilitic  Arthritis. 

From  simple  inflammation  of  a  joint,  up  to  its  complete  destruction  or 
ankylosis,  the  various  clinical  t\^es  met  with  may  be  caused  by  syphilis,  and  are, 
per  se,  indistinguishable  from  the  same  conditions  produced  by  other  causes. 

The  inflammation  may  commence  in  the  synovial  membrane,  in  the  capsule, 
or  in  the  articular  surfaces  of  the  bones.  Slight  inflammation  of  the  synovial 
membrane  and  capsule  may  produce  no  other  sign  or  symptom  than  pain.  ^  When 
the  inflammation  commences  in  the  synovial  membrane,  as  a  rule  fluid  is  excreted 
into  the  joint,  and  there  is  one  clinical  condition  which  is  sometimes  caused  by 
s}^hilis,  in  which,  w-ithout  warning  or  pain,  the  joint  suddenly  and  very  quickly 
becomes  distended  with  fluid.  The  condition  is  called  Hydrops  articuli,  and  the  knee 
joint  is  ahnost  invariably  the  joint  affected.  In  some  of  these  cases,  the  fluid 
disappears  as  quickly  as  it  came,  and  then  is  liable  to  recur  without  any  provocation. 
In  those  cases  in  which  the  inflammation  is  very  acute,  and  in  which  one  or  more 
joints  are  affected,  the  patient  usually  looks  extremely  ill,  emaciated,  and  anaemic. 
There  is  always  marked  wasting  of  the  muscles  above  and  below  the  affected  joint, 
To  mv  mind  it  is  very  odd  that  patients  with  a  s}'philitic  arthritis,  and  still  more  so 


SYPHILIS   OF   THE    BONES   AND    JOINTS.  173 

is  it  the  case  with  a  gonococcal  arthritis,  should  generally  look  so  desperately  ill  and 
lose  so  much  weight.  I  can  neither  give  a  good  reason,  nor  can  I  find  one  in  the 
literature.  It  is  absolutely  impossible  to  difierentiate  between  a  syphilitic  and  a 
gonococcal  arthritis.  If  the  patient  has  a  discharge,  and  signs  of  an  old  prostatitis 
can  be  detected  by  a  rectal  examination,  the  diagnosis  is  often  obvious  ;  but,  not 
infrequently,  a  patient  may  have  a  severe  gonococcal  polyarthritis,  after  all  signs 
of  gonorrhoea  have  disappeared  from  his  urinary  tract. 

A  monoarticular  gonococcal  arthritis  frequently  ends  in  an  Arthritis  deformans. 
A  syphilitic  arthritis  does  not  do  so. 

There  is  still  much  division  in  opinion  as  to  whether  syphilis  can  be  a  cause 
of  Arthritis  deformans.  Personally,  I  think  it  is  very  doubtful,  and  in  every  case 
of  Arthritis  deformans  which  I  have  seen  in  syphilitics,  the  patients  had  all  had 
gonorrhoea  and  gonococcal  arthritis,  which,  in  my  opinion,  was  the  cause  of  the 
Arthritis  deformans.  I  recently  had  two  cases  of  Arthritis  deformans  affecting  both 
hip  joints. 

Both  these  cases  had  had  gonorrhoea  and  syphilis,  and  in  both  the  Wasser- 
mann  reaction  was  positive.  In  the  one  case,  the  process  was  early  in  both  joints, 
therefore  some  improvement  could  be  expected  from  treatment.  Salvarsan, 
mercury  and  iodides  had  no  influence  whatever.  The  patient  began  to  improve, 
only  when  gonococcal  vaccines  had  been  administered. 

In  the  other  case,  one  hip  showed  all  the  classical  signs  of  advanced  Arthritis 
deformans,  while  the  process  in  the  other  had  only  just  commenced.  Here,  again, 
benefit  resulted  from  gonococcal  vaccines,  and  not  from  anti-syphilitic  treatment. 

That  familiar  condition,  so  commonly  seen  in  tubercular  patients,  to  which  the 
name  of  Tumor  albus  has  been  given,  may  also  be  met  with  as  a  late  manifestation 
of  syphilis,  and,  from  an  examination  of  the  joint  alone,  the  two  diseases  cannot  be 
differentiated.  This  fact  has  led  some  clinicians  (who  cannot  make  a  mistake),  to 
diagnose  many  cases  of  Tumor  albus  as  a  mixture  of  tubercle  and  syphilis. 

In  all  these  very  difficult  cases,  the  best  means  of  arriving  at  a  correct  diagnosis 
is  to  give  an  injection  of  salvarsan.  The  treatment  test  is  far  superior  to  any 
other,  as  I  have  frequently  seen  patients  with  symptoms  which  might  not  be 
svphilitic  give  a  positive  Wassermann  reaction,  when  the  lesions  were  really  due 
to  causes  other  than  syphilis.  It  should  always  be  remembered,  that  a  patient  who 
has  had  syphilis  is  just  as  prone  to  contract  other  diseases  as  a  patient  who  has 
not  been  so  infected. 

Syphilitic  lesions  of  bursae  and  tendons  are  more  or  less  curiosities,  and,  as 
they  have  no  distinguishing  features,  it  does  not  appear  necessary  to  discuss  them 
further. 


CHAPTER  XXI. 
SYPHILIS  OF  THE   ABDOiHNAL  YISCEEA. 

Oue  of  the  least  studied  chapters  of  syphihs,  is  that  deaUug  with  syphiUs  of  the 
abdominal  viscera.  This  omission  is  largely  due  to  the  fact  that  the  correct  diagnosis 
is  not  made,  until  the  patient  has  reached  the  post-mortem  room.  Many  other 
cases  escape  detection,  because  they  recover  from  an  abdominal  section  which  has 
been  performed  for  an  inoperable  maUguant  growth. 

Oesophagus  and  Stomach. 

S}^hilis  of  the  oesophagus  is  undoubtedly  very  rare,  and  the  only  case  I  have 
seen  was  in  a  health3'-looking  young  woman,  who  was  operated  upon  for  a  supposed 
carcinoma  of  the  cardiac  end  of  the  stomach.  The  operation  revealed  a  diffuse 
induration  of  the  cardiac  ends  of  the  oesophagus  and  stomach,  and  the  abdominal 
wound  was  closed,  with  the  idea  that  the  lesion  was  cancerous.  The  patient  was 
given  some  potassimn  iodide,  and  from  that  time  onward  made  an  uninterrupted 
recovery.     Cases  have  been  described  of  syphihtic  stenosis  of  the  oesophagus. 

Syphihs  of  the  stomach  is  a  great  deal  more  common  than  is  generally  supposed. 
A  catarrh  in  the  generalisation  stage  can  sometimes  be  ascertained,  if  every  patient 
be  thoroughly  examined.  The  diagnosis  is  admittedly  difficult,  owing  to  the  fact 
that  anaemia  may  be  primarily  responsible  for  the  indigestion,  h^'peracidity, 
sickness  and  loss  of  appetite ;  these  being  the  main  symptoms  complained  of.  If 
mercury  has  been  given  internally,  it  is  impossible  to  say  how  far  it  is  responsible 
for  the  gastric  trouble. 

In  the  later  stages  of  syphihs,  the  disease  may  produce  a  diffuse  infiltration  of 
the  walls  of  the  stomach.  I  have  seen  such  a  case  which  recovered  under  anti- 
syphihtic  treatment,  after  the  diagnois  of  sarcoma  had  been  made  at  an  abdominal 
section. 

The  infiltration  may  affect  the  pylorus ;  indeed,  it  is  frequently  limited  to 
this  portion  of  the  stomach. 

Case  23. — A  medical  man,  aged  36,  came  to  me  for  some  injections  of  salvarsan. 


SYPHILIS    OF   THE   ABDOMINAL    VISCERA.  175 

because  he  had  syphilis.  He  informed  me  that  he  had  a  sweUiug  over  the  pyloric 
end  of  the  stomach,  and  it  was  quite  distinct  upon  palpation,  and  had  aroused  the 
suspicion  of  carcinoma  in  the  minds  of  some  of  the  surgeons  whom  he  had  con- 
sulted. He  had  been  strongly  advised  to  have  a  gastro-jejunostomy  performed,  but, 
knowing  that  he  had  had  syphilis,  he  thought  he  would  try  salvarsan  first.  After  a 
few  injections,  the  swelling  completely  disappeared. 

Since  then  I  have  seen  three  other  cases  of  a  swelling  in  the  pyloric  region,  in 
young  and  apparently  healthy  individuals,  in  all  of  whom  the  symptoms  and 
swelUng  vanished  under  salvarsan.  It  is  extremely  probable  that  many  of  the 
cures,  in  young  middle-aged  persons,  which  have  resulted  from  short  circuiting, 
are  not  due  to  the  operation,  but  to  the  spontaneous  disappearance  of  the  lesion, 
as  some  of  the  late  symptoms  of  syphilis  are  occasionally  wont  to  do. 

SyphiUs  may  also  cause  ulceration  of  the  stomach  ;  there  may  be  a  single 
ulcer,  or  several.  Such  cases,  again,  are  not,  as  a  rule,  diagnosed  until  after  death, 
when  it  is  seen  that  the  syphilitic  ulcer  is  different  from  the  usual  type  of  gastric 
ulcer. 

A  syphihtic  ulcer  is  sharply  circumscribed.  There  is  no  surrounding  inflamma- 
tion, it  is  never  terraced,  and,  as  a  rule,  the  edge  is  raised  and  thick. 

As  a  rule,  syphilitic  ulcers  of  the  stomach  heal  and  leave  a  scar  ;  the  scar  causes 
contraction,  and  usually  the  patient  suffers  from  chronic  indigestion. 

In  most  cases  of  gastric  ulcer,  syphilis  should  be  borne  in  mind,  because,  if 
syphihs  is  the  cause,  the  cases  recover  rapidly  under  appropriate  treatment. 
Haemorrhage  is  not  a  common  sviuptom,  for  the  simple  reason  that  the  ulcer  is 
usually  a  necrosis  of  that  area  which  was  fed  by  a  vessel  which  had  become  occluded 
by  inflammation.  Perforation  practically  never  occurs,  as  the  outer  portion  of  the 
wall  and  the  peritoneum  remain  unaffected. 

A  great  deal  of  work  on  the  chemical  analysis  of  the  gastric  contents  in  cases 
of  syphihs  of  the  stomach  still  remains  to  be  done.  My  experience  in  this  direction 
is  very  limited,  but,  from  the  few  examinations  which  have  been  made,  a  typical 
feature  seems  to  be  the  decrease  in  the  hydrochloric  acid  content. 

Hausmann,^  who  has  made  a  special  study  of  syphilis  of  the  abdominal  organs, 
mentions  the  following  points  in  the  differential  diagnosis  between  syphilis  and 
other  diseases  of  the  stomach  : — 

(1)  A  normal  or  increased  HCl-content  excludes  gxunma  of  the  stomach, 
gummatous  ulceration,  syphilitic  hyperplasia,  and  shrunken  stomach. 

(2)  Nocturnal  gastric  pains,  with  anacidity,  is  in  favoiu-  of  syphilis  of  the 
stomach,  or  of  a  syphilitic  retroperitoneal  tumour,  but  it  does  not  exclude  ordinary 
pyloric  stenosis. 

M 


176  THE    BIOLOGY,    CLINICAL    ASPECT   AND    TREATMENT   OF   SYPHILIS. 

(3)  Characteristic  symptoms  of  gastric  ulcer,  associated  with  anacidity,  favours 
the  diagnosis  of  gmumatous  ulcer. 

(4)  A  palpable  pyloric  swelling,  with  anacidity  and  absence  of  the  symptoms 
of  stenosis,  and  a  negative  blood  test  in  the  stomach  secretion  and  in  the  faeces, 
points  to  there  being  a  diffuse  gummatous  infiltration  of  the  pylorus. 

(5)  In  all  cases  of  shrunken  stomach,  the  diagnosis  of  sypjiihs  must  be  seriously 
borne  in  mind. 

In  every  case  in  which  pains  in  the  stomach  are  complained  of,  the  possibility 
of  these  pains  being  the  gastric  crises  of  degenerative  myelitis  should  always  be 
considered.  I  know  of  four  patients  who  have  had  a  gastro-jejunostomy  performed, 
when  their  symptoms  were  really  those  of  degenerative  myelitis  ;  one  of  these 
was  operated  upon  twice,  and  I  have  been  fortunate  enough  to  save  three  others 
from  suffering  a  similar  fate. 

Syphilis  of  the  Intestines. 

In  the  acute  stage  of  syphilis,  there  may  be  a  catarrh  of  the  duodenum,  which 
is  nearly  always  associated  with  a  catarrh  of  the  bile  ducts,  without  and  within 
the  liver,  the  result  being  that  the  patient  becomes  jaundiced. 

Doubtless  a  catarrh  of  the  rest  of  the  intestinal  tract  occurs,  but  its  diagnosis 
would  be  a  matter  of  extreme  difficulty.  The  Condylomata  lata  which  one  so 
•commonly  sees  around  the  anus  may  extend  up  the  anal  canal,  but,  as  a  rule,  they 
give  rise  to  no  symptoms  unless  they  ulcerate,  and  then  give  rise  to  a  stricture,  a 
sequela  which  is  very  rare.  Syphihs  of  the  intestines  is  more  common  in  the  congenital 
than  in  the  acquired  form,  hence,  in  acquired  syphilis,  one  would  expect  to  find  the 
intestines  affected  in  the  late  stages,  which  is  the  case.  The  commonest  syphilitic 
lesion  of  the  gut  is  a  diffuse  syphihtic  infiltration  of  the  wall.  Occasionally  the 
infiltration  is  localised  and  annular,  and  then  it  quickly  gives  rise  to  narrowing  of 
the  liunen,  and  to  stenosis.  Such  cases,  when  operated  upon,  are  almost  invariably 
regarded  as  carcinomata.  If  the  stenosis  is  of  long  standing,  naturally  the  mucous 
membrane  ulcerates,  but  in  all  these  cases  of  syphilitic  infiltration  of  the  gut  wall 
the  mucous  membrane  is  intact,  and  only  becomes  secondarily  involved.  The 
diffuse  form  is  usually  diagnosed  as  sarcoma. 

Syphihs  may  affect  the  tissue  subjacent  to  the  peritoneum.  The  peritoneum 
becomes  secondarily  involved,  and  adhesions  are  formed  between  the  affected  area 
and  the  surrounding  structures. 

I  have  seen  a  case  of  this  sort,  involving  the  under  surface  of  the  liver,  the 
duodenum,  and  the  pancreas.  I  also  have  notes  of  another  case,  in  which  the  pyloric 
end  of  the  stomach  was  bound  down  to  the  viscera  around  by  adhesions. 


SYPHILIS   OF   THE    ABDOMINAL    VISCERA.  177 

This  is  probably  the  pathology  of  the  so-called  syphihtic  stricture  of  the 
rectum. 

Sj'philitic  stricture  of  the  rectum  is  much  more  common  in  women  than  in 
men,  and,  in  some  cases,  the  whole  jielvis  seems  to  be  filled  with  a  dense  mass  of 
infiltrated  tissue.  It  is  the  contraction  of  this  tissue  which  leads  to  the  narrowing 
of  the  lumen  of  the  bowel,  and  here  again  any  ulceration  of  the  raucous  membrane 
is  the  result,  and  not  the  cause.  Gummatous  ulceration  of  the  bowel  is  never 
diagnosed  except  post-mortem,  i.e.,  when  it  affects  any  part  of  the  bowel  other  than 
the  rectum. 

The  gumniata  are  almost  invariably  multiple.  They  are  sharply  circum- 
scribed, have  raised  edges,  and  practically  no  surrounding  inflammation.  They 
do  not,  as  a  rule,  affect  the  Peyer's  patches,  and  they  often  heal  spontaneously. 

Gummatous  ulceration  of  the  rectum  may  lead  to  stricture,  and  an  important 
point  to  remember  in  these  cases  is,  that  if  the  rectal  stricture  is  due  to  gummatous 
ulceration,  i.e.,  if  it  is  a  primary  lesion  of  the  mucous  membrane,  the  chances  are 
that  there  are  gummata  higher  up  in  the  gut.  If  there  are  gummata  higher  up 
in  the  gut,  there  may  also  be  a  stricture  higher  up. 

Unfortunately,  these  cases  do  not  give  rise  to  symptoms  until  the  syphilitic 
lesion  has  healed,  and  its  place  has  been  taken  by  contracting  fibrous  tissue, 
therefore  surgical  interference  is  usually  called  for. 

Syphilis  of  the  Liver. 

Cholangitis  is  the  connnonest  early  syphilitic  lesion  of  the  liver,  and  it  is 
extraordinary  how  very  early  in  the  disease  the  jaundice  may  be  very  severe.  Not 
a  moment  should  be  lost  in  giving  neo-salvarsan  in  these  cases.  In  the  early  days 
of  "  606,"  when  jaundice  was  not  a  very  uncommon  sequence  of  its  administration, 
syphilitic  jaundice  was  regarded  as  a  contraindication  to  its  employment,  but  now 
it  is,  correctly,  a  strong  indication. 

Acute  yellow  atrophy  of  the  liver,  though  due  more  often  to  other  conditions, 
is  sometimes  caused  by  syphilis  in  its  early  stages,  and  even  such  a  fatal  condition 
as  this  may  be  saved,  if  neo-salvarsan  is  used  energetically,  and  as  quickly  as  possible 
after  the  onset.  The  late  syphilitic  lesions  of  the  liver  are  very  easy  to  understand, 
if  it  be  remembered  that  the  disease  begins  in  the  connective  tissue,  either  between 
the  acini  or  between  the  cells  themselves. 

The  interstitial  or  indurative  hepatitis  may  be  diffuse  or  locahsed.  If 
localised,  it  may  be  single  or  multiple. 

The  diffuse  form  gives  rise  to  a  hypertrophic  cirrhosis,  which  cannot  be 
distinguished  from  a  similar  condition  produced  by  other  causes.     As  the  fibrous 

m2 


178  THE    BIOLOGY,    CLINICAL   ASPECT   A?JD    TREATMENT    OF   SYPHILIS. 

tissue  contracts,  the  blood  supply  to  the  parenchyma  cells  will  be  diminished,  and 
therefore  many  of  the  latter  will  degenerate.  The  liver  gets  smaller  and  smaller — 
the  so-called  atrophic  cirrhosis. 

The  localised  form  varies  enormously  in  size.  Usually  the  parenchyma  cells 
completely  degenerate,  and  the  lesion  becomes  a  giimma. 

This  is  also  the  pathology  of  the  multiple  localised  lesions.  Those  lesions  on 
the  surface,  owing  to  the  contraction  of  the  fibrous  tissue,  often  have  a  marked 
depression  in  their  centre. 

It  sometimes  happens  that  only  one  lobe  is  affected.  Say,  for  sake  of  argument, 
that  it  is  the  left,  then  the  right  lobe  will  hypertrophy — a  compensatory  hyper- 
trophy. 

Since  the  right  lobe  is  more  easily  palpated  than  the  left,  a  mistake  may  easily 
be  made  in  diagnosing  a  compensatory  hj'pertrophic  right  lobe  as  hj'pertrophic 
cirrhosis.  Most  cases  of  sj-philis  of  the  liver  run  a  symptomless  course,  and  are 
not  diagnosed  until  after  death,  a  circumstance  which  gives  the  clinician  the  idea 
that  S3^hilis  of  the  liver  is  rarer  than  it  really  is. 

If  Glisson's  capsule  is  affected,  and  there  is  a  marked  perihepatitis,  pain  is  a 
very  common  symptom.  The  pain  is  independent  of  taking  food,  and  it  is  increased 
on  deep  breathing  and  coughing. 

Pain  is  a  good  sign,  as  it  shows  that  the  perihepatitis  is  acute,  and  therefore 
much  is  to  be  expected  from  treatment. 

Vomiting  is  a  common  symptom,  but  possibly  the  most  important  symptom 
is  intermittent  fever. 

This  intermittent  fever  is  often  the  only  spiiptom  which  the  patient  develops 
and  for  which  he  seeks  advice,  so  that  many  clinicians  have  described  a  condition 
to  which  they  have  given  the  name  of  tertiary  syphilitic  fever. ^ 

I  had  one  case  which  had  been  diagnosed  for  months  as  malaria.  Tvphoid 
fever,  mahgnant  endocarditis,  febrile  cholelithiasis,  pulmonary  tuberculosis  (as 
the  spitting  up  of  blood  sometimes  occurs),  and  lymphadenoma  may  easily  be 
mistaken  for  late  syphihtic  fever. 

I  had  another  interesting  case,  in  which  the  febrile  attacks  were  accompanied 
by  haemoglobinuria. 

Late  syphilitic  fever  is  best  diagnosed  by  the  rapidity  with  which  it  disappears 
under  anti-syphilitic  treatment. 

Ascites  is  not  a  commbn  comphcation  of  syphihtic  cirrhosis. 

Alimentary  galactosuria  is,  according  to  Bauer,^  a  frequent  sign  of  syphilitic 
hepatitis  ;  and  so  also  is  urobilinuria,  and  the  occurrence  of  both  of  these  points 
to  damage  of  the  parenchyma  cells. 


SYPHILIS   OF   THE    ABDOMINAL    VISCERA.  179 

In  practically  all  the  cases  of  tertiary  syphilitic  fever,  the  spleen  is  enlarged 
as  well  as  the  liver,  and  one  of  the  distinguishing  features  between  syphilitic  cirrhosis 
and  alcoholic  cirrhosis  is  that,  in  the  former,  there  is  more  often  an  enlargement 
of  the  spleen  than  ascites,  while  in  the  latter,  the  reverse  is  the  case. 


Syphilis  of  the  Pancreas. 

What  has  been  stated  re  the  interstitial  nature  of  the  syphilitic  process  in  the 
liver,  applies  also  to  the  pancreas.  In  most  cases  of  syphilitic  disease  of  the 
pancreas,  it  is  only  the  head  of  the  organ  which  is  involved. 

Syphilitic  pancreatitis  usually  leads  to  the  formation  of  adhesions  which 
involve  all  the  neighbouring  structures,  so  the  clinical  picture  is  often  a  varied  one. 
The  following  is  a  good  example  of  a  case  of  syphilitic  disease  of  the  head  of  the 
pancreas  : — 

Case  2i. — Patient  was  a  medical  man,  aged  35,  who  contracted  syphilis  three 
years  before  onset  of  present  trouble.  Treatment  had  been  more  or  less  con- 
tinuous ;  the  notes  are  best  given  as  he  wrote  them  out  for  me. 

"  In  January,  1910,  I  first  commenced  to  experience  attacks  of  pain  in  the 
epigastriinn.  The  early  attacks  took  the  form  of  a  didl  ache  across  the  epigastrium, 
commencing  about  midday  after  having  been  at  work  for  two  or  three  hours.  Pain 
would  gradually  become  worse,  till  I  was  forced  to  lie  down,  which  would  almost 
immediately  relieve  me  of  further  pain.  Minor  attacks  of  this  pain  were  very 
frequent,  and  on  a  few  occasions  severe  attacks  were  experienced,  which  necessitated 
my  lying  up  for  a  week.  The  pain  was  always  of  a  dull,  aching  character,  never 
localised,  but  indefinite  and  extending  across  the  epigastrium.  It  was  seldom 
accompanied  by  any  other  symptoms,  except  occasionally  by  a  mild  nausea  and 
a  peculiar  chilly  feehng. 

"  The  attacks  were  in  no  way  connected  with  food.  During  January, 
February,  and  March,  1911,  the  attacks  became  so  bad  that  in  April  I  left  for 
home.  The  attacks  occurred  daily,  and  were  now  almost  invariably  associated 
with  nausea.  In  May,  jaundice  developed  which  lasted  three  weeks,  and  diagnosis 
was  then  made  of  catarrhal  inflanimation  of  gall-bladder  and  duodenum.  X-rays 
showed  nothing  abnormal.  Pains  continued  throughout  June  and  July,  when  I 
consulted  Mr.  ,  who  diagnosed  duodenal  ulcer. 

"  In  July  I  was  obliged  to  return  to  duty,  but,  as  trouble  persisted,  I  came 
home  again  in  November,  1911,  and  was  operated  upon  January,  1912,  by  Mr. 
.     No  ulcer  of  the  stomach  or  duodenum  was  found,  and  appendix  appeared 


normal.     Gall-bladder   was  attached  to  all  surrounding  structures  by  adhesions, 


180  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

and  there  was  a  typical  chronic  pancreatitis,  which  had  previously  been  suggested 
as  a  result  of  Cammidge's  tests.  Following  the  operation,  I  remained  free  of 
sj-mptoms  till  March,  1912,  when  they  all  returned,  and  three  months  later  they 
were  worse  than  they  had  ever  been  before." 

In  September,  1912,  I  saw  the  f)atient,  and,  as  the  Wassermann  reaction 
was  positive,  I  gave  several  injections  of  neo-salvarsan,  and  followed  up  the  treatment 
with  mercury  and  iodides.  After  the  first  injection  the  symptoms  vanished,  and 
patient  has  been  perfectly  well  since. 

Intermittent  glycosuria  may  be  the  only  symptom  of  a  syphihtic  affection 
of  the  pancreas,  but  it  must  be  remembered  that  not  every  case  of  syphilitic 
glycosuria  is  of  pancreatic  origin  ;  for  instance,  it  may  be  a  symptom  of  an 
intracranial  lesion. 

A  thorough  examination  of  the  faeces  and  urine  is  necessary  in  all  cases  of 
suspected  implication  of  the  pancreas. 

Syphilis  of  the  Spleen. 

An  enlargement  of  the  spleen  in  congenital  syphilis  is  a  very  well-known  fact, 
but  that  the  spleen  is  often  enlarged  in  early  sj'philis,  few  have  noted.  The  spleen 
is  nothing  more  nor  less  than  a  huge  lymphatic  gland.  A  general  enlargement 
of  the  lymphatic  glands  is  one  of  the  commonest  and  earUest  signs  of  syphilis, 
therefore,  if  one  thinks,  it  would  be  only  too  reasonable  to  expect  a  hyperplasia  of 
the  spleen  in  the  early  stage. 

Syphilitic  splenitis,  in  conjunction  with  syphilitic  hepatititis,  has  already 
been  referred  to,  and  the  part  that  syphilis  plays  in  the  enlargement  of  the  .spleen, 
in  cases  of  lymphocytomata,  will  be  more  fully  dealt  witli  in  Chapter  XLVI. 

Although  Banti  himself  was  against  the  view  that  syphihs  played  a  part  in 
the  aetiology  of  the  disease  which  goes  by  his  name  (splenitis,  anaemia,  cirrhosis 
of  the  liver,  and  ascites),  there  can  be  no  doubt  now  that  syphilis  is  sometimes  the 
cause. 

Syphilis  of  the  Peritoneum,  etc. 

Retroperitoneal  and  mesenterial  swelhngs  may  sometimes  be  of  syphilitic 
origin,  and  the  site  of  the  trouble  is  usually  in  the  lymphatic  glands.  The  swelling 
may  sometimes  reach  an  enormous  size.  An  analogous  condition  occurs  in  the 
mediastinum,  and  a  glandular  swelhng  in  this  situation  is  usually  mistaken  for  an 
aneurysm. 

There  is  an  extremely  interesting  condition  which  is  sometimes  met  with  in 
syphilis,  in  which  the  patient  has  a  pseudo-chylous  ascites. 


SYPHILIS    OF   THE    ABDOMINAL   VISCERA.  181 

Though  not  a  true  syphilitic  disease  of  the  peritoneum,  it  may  occur  in  cases 
in  which  no  trouble  of  an  abdominal  organ  can  be  traced,  although  it  is  usually 
secondary  to  a  lesion  of  an  abdominal  viscus. 

The  chemical  and  physical  properties  of  the  fluid  from  cases  of  chylous  and 
pseudo-chylous  ascites,  have  been  so  ably  worked  out  by  Mackenzie  Wallis  and 
Scholberg,*  ^  that  anyone  who  is  interested  in  this  subject  should  refer  to  them. 

'  Hausmann     (1913),     "  Die     Luet.    Erkrankungen     dcr     Bauchorgane."       C.     Marhold. 

Halle  a.  S. 
2  Parkes  Weber  (1907),  "  Lancet,"  i,  728. 
'  Bauer  (1910),  "  Lues  unci  innere  Medizin." 

*  .Mackenzie  Wallis  and  Scholberg  (1910),  "  The  Quarterly  .Journ.  of  Med.,"'  iii,  301. 

*  Mackenzie  Wallis  and  Scholberg  (1911),  "The  Quarterly  Journ.  of  Med.,"  iv,  1.53. 


CHAPTER  XXII. 
EXAMINATION  OF  THE  CEREBROSPINAL  FLUID. 

For  drawing  off  the  cerebro-spinal  fluid,  I  prefer  Barker's  needle  to  any  other. 
The  patient  i.s  made  to  lie  on  his  left  side,  on  a  hard  conch  for  preference,  so  as  to 
avoid  a  spinal  curve.  The  knees  should  be  well  drawn  up,  the  left  arm  and  shoulder 
pulled  down,  and  the  head  and  neck  bent  towards  the  knees.     The  observer  should 


B.arker's  Luml.iar  Puncture  Needles. 


then  see  that  the  back  is  straight,  i.e.,  that  the  two  halves  of  the  pelvis  are  lying 
in  the  same  perpendicular. 

The  highest  point  of  the  right  iliac  crest  is  ascertained,  and  then  the  intra- 
vertebral  space  found,  which  lies  to  the  sacral  side  of  a  line  drawn  across  the  back 
from  this  point.  The  best  intra  vertebral  space  is  the  one  between  the  fourth  and 
lifth  lumbar  vertebrae,  and  it  is  not  in  the  same  position  in  everybody. 

It  is  scarcely  ever  on  the  line  from  the  highest  point  of  the  iliac  crest,  but 
almost  invariably  just  to  the  sacral  side,  or  well  to  the  sacral  side  of  it. 

After  an  injection  of  a  local  anaesthetic  (0'5  per  cent,  novocain),  the  forefinger 
of  the  left  hand  is  placed  on  the  spine  of  the  fourth  lumbar  vertebra,  and  the  needle 
is  inserted  in  the  middle  line  by  the  side  of  the  finger.     The  needle  is  then  directed 


EXAMINATION   OF   THE   CEREBRO-SPINAL   FLUID.  183 

horizontally  imvards,  until  the  canal  has  been  reached.  If  the  point  of  the  needle 
impinges  on  bone,  it  should  be  withdrawn,  and  another  direction  tried.  An  experienced 
observer  knows  by  the  feel  when  he  has  pierced  the  dura  mater.  If  the  needle  has 
entered  the  canal  too  low  down,  the  patient  experiences  a  sharp  pain  down  one  of 
his  legs.  Occasionally  the  dura  mater  becomes  attached  to  the  cord  higher  up 
in  some  individuals  than  in  others,  so  it  is  always  wise  to  pierce  the  skin  near  the 
spine  of  the  fourth  lumbar  vertebra.  Personally,  I  think  it  is  easier  to  insert  the 
needle  in  the  middle  line  than  half  an  inch  below,  the  point  that  is  usually  advised. 

However  careful  or  expert  one  may  be,  difficulties  in  tajjping  the  theca  may 
be  met  with,  and  the  operation  is  similar  in  this  respect  to  venepuncture.  Men 
who  have  had  a  very  wide  experience  of  giving  intravenous  injections  know  ordy 
too  well  that  they  may  be  baffled  now  and  again. 

If  the  cerebro-spinal  fluid  is  being  withdrawn  for  testing  purposes,  and  a 
drop  of  blood  comes  through  the  needle,  the  needle  should  be  withdrawn  and  the 
operation  postponed  for  a  week  or  two. 

A  collodion  dressing  is  all  that  is  required  after  the  needle  has  been  withdrawn. 
A  syphilologist  may  be  called  upon  to  tap  the  theca  for  three  purposes:  (1)  for 
testing  ;   (2)  for  relie^^ng  pressure  ;   (.3)  for  injection. 

If  the  fluid  is  only  being  withdrawn  for  testing  purposes,  as  little  should  be 
taken  as  possible,  becau.se,  even  if  the  quantity  is  made  up  by  injecting  saline, 
excruciating  headaches,  which  persist  from  one  to  seven  daj's,  cannot  always  be 
avoided. 

Headaches  are  certainly  less  frequent  if  saline  is  injected,  and  they  appear 
to  be  less  frequent  in  those  cases  in  which  the  central  nervous  system  has  already 
been  attacked. 

If  the  patient  is  kept  in  bed  after  a  lumbar  puncture,  and  the  head  is  allowed 
to  rest  on  a  lower  plane  than  the  feet,  headaches  are  rare  ;  but  since  lumbar 
puncture  has  become  more  or  less  a  routine,  I  always  perform  the  operation  in  my 
room,  and  let  the  patient  return  home  afterwards.  I  usually  arrange  to  do  the 
operation  in  the  evening,  and  send  the  patient  straight  home  to  bed,  with  the  request 
to  raise  the  foot  of  the  bed. 

If  lumbar  puncture  is  done  to  relieve  pressure,  the  patient  is  certain  to  be  in 
bed,  and  the  quantity  drawn  off  does  not  matter  ;  30  to  40  c.c.  can  be  withdrawn 
comfortably. 

When  an  operation  for  pressure  has  to  be  performed, the  case  is  almost  invariably 
one  of  pachymeningitis,  for  which  salvarsan  has  been  given.  Salvarsan  causes 
reactionary  inflammation;  reactionary  inflammation  in  an  already  thickened  dura- 
mater  may  be  just  sufficient  to  cause  compression.    In  the  case  of  pach^mieningitis, 


184  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

the  symptoms  of  compressiou,  i.e.,  loss  of  consciousness,  etc.,  usually  set  in  between 
48  and  72  hours  after  the  second  or  third  intravenous  injection  of  salvarsan. 
Lumbar  puncture  may  relieve  these  cases  at  once.  Since  the  reactionary  inflam- 
mation is  largely  due  to  a  vascular  dilatation,  injections  of  adrenalin  are  very  useful. 

Although  a  recurrence  of  the  compression,  after  subsequent  injections  of 
salvarsan,  is  not  likely  to  occur,  a  subcutaneous  injection  of  adrenalin  will  certainly 
minimise  the  chance,  and  it  may  be  administered  prior  to  the  injection,  should  the 
observer  require  more  self-confidence. 

Pachymeningitis  is  a  late  symptom  of  syphilis  ;  but  symptoms  of  compression, 
which  usually  start  like  Jacksonian  epilepsy,  may  occur  after  salvarsan  in  early 
syphilis.  The  attack  generally  sets  in  about  48  hours  after  the  second  injection, 
and  is  due  to  a  haemorrhagic  encephalitis. 

This  form  of  haemorrhagic  encephalitis  is  a  reactionary  inflammation  of  the 
vessels  in  the  cortex  of  the  brain,  which  have  been  affected  by  syphilis.  A  lumbar 
puncture  in  such  a  case  is  valueless,  so  is  trephining,  the  only  remedy  of  any  use 
being  adrenalin. 

When  the  theca  has  been  tapped  for  injection  purposes,  it  is  usually  for  the 
injection  of  salvarsanised  serum,  and  will  therefore  be  described  in  the  chapter 
dealing  with  treatment  (Chapter  XXIX). 

The  first  thing  one  notes  in  doing  a  lumbar  puncture  is  the  pressure  at  which 
the  fluid  flows  through  the  needle. 

Not  too  nuich  reliance  should  be  placed  upon  pressure,  since  it  varies  in  normal 
individuals.  It  is  usually  raised  in  syphilitic  diseases  of  the  central  nervous  system, 
and  is  often  markedly  raised  in  patients  whose  nervous  system  has  not  been  involved, 
but  who  have  had  a  series  of  intravenous  injections  of  salvarsan. 

AVhen  the  fluid  has  been  collected,  its  colour  is  then  noted.     Normal  cerebro 
spinal  fluid  is  clear,  like  water. 

Blood. 

Blood  in  the  cerebro-spinal  fluid  may  come  either  from  the  skin  and  vessels, 
and  may  get  into  the  lumbar  puncture  needle  before  the  dura  has  been  penetrated, 
or  blood  may  appear  as  a  result  of  some  severe  nervous  lesion. 

The  differentiation  is  simple,  since  in  the  former  case  all  the  blood  is  deposited 
on  centrifugiug,  whilst  in  the  latter,  a  yellowish  or  brownish  tinge  of  the  cerebro- 
spinal fluid  remains  behind,  and  gives  both  the  spectroscopic  and  benzidin  tests  for 
blood. 

Nonne  ^  -  reports  a  case  where  blood  occurred  in  a  patient  with  syphilitic 
meningo-encephalitis,  but  the  presence  of  blood  is  not  diagnostic  of  a  sjrphilitic 


EXAMINATION    OF   THE    CEREBRO- SPINAL   FLUID.  185 

condition,  since  it  may  be  found  in  any  case  of  acute  meningo-encephalitis  or  Pachy- 
meningitis liaemorrliagica. 

In  some  cases  of  old  standing  active  syphilitic  cerebro-spinal  meningitis,  I  have 
not  infrequently,  when  looking  into  the  column  of  fluid  from  above,  noticed  a  faint 
yellowish  tinge. 

Cells. 

The  cells  are  next  counted,  and  this  can  be  managed  with  an  ordinary  Thoma- 
Zeiss  haemocytometer,  but  the  best  method  is  that  known  as  the  Fuchs-RosenthaP 
counting  method. 

The  Fuchs-Rosenthal  counting  chamber  is  16  mm.  square  and  0"2  mm.  deep, 
hence  it  differs  from  the  ordinary  Thoma-Zeiss  blood-counting  chamber,  in  that 
the  latter  is  only  1  mm.  square  and  0 '  1  mm.  deep.  The  resulting  count  with  the 
latter  gives  the  number  of  cells  in  yV  c.mm.  of  blood  ;  while  the  former  gives  the 
number  of  cells  in  -V~  c.mm.     This  obviously  reduces  the  errors  in  counting. 

The  fluid  must  be  examined  as  soon  as  possible  after  withdrawal,  as  the  cell 
content  suffers  through  standing.  The  fluid  should  also  be  well  shaken,  so  as  to 
produce  an  even  distribution  of  the  cells. 

The  cells  can  be  examined  unstained  or  stained  ;  if  the  latter,  then  the  best 
stain  to  use  is  the  following  : — 

Methyl  violet         0  0.5  gnu. 

Glacial  acetic  acid  ...         ...         ...         ...     0-50     „ 

Distilled  water       24-45  c.c. 

Unfortunately,  this  stain  requires  to  be  freshly  prepared,  as  fungi  quickly 
develop  in  it. 

The  cells  which  may  be  found  in  the  cerebro-spinal  fluid  are  :  (1)  poly- 
morphonuclear leucocj-tes  ;  (2)  lymphocytes  ;  (.3)  plasma  cells  ;  (4)  embryo 
lymphocytes  ;   (5)  endothelial  cells. 

The  eight  cells  per  cubic  millimetre  which  may  be  found  in  normal  cerebro- 
spinal fluid  are  mostly  all  Ipnphocytes. 

Polymorphonuclear  leucocytes  are  found  most  abundantl)'  in  such  conditions 
as  meningococcal  meningitis,  etc.,  and,  if  they  occur  in  syphilitic  infections,  they 
either  indicate  that  there  is  a  secondary  infection  or  that  the  lesion  is  a  meningeal 
one.  Lymphocytes  are  the  cells  most  connnonly  found  in  syphilis,  and  as  many 
as  1,000  or  more  per  cubic  millimetre  may  be  present. 

The  presence  of  a  lymphocyto.sis  is  not  diagno.stic  of  the  nervous  lesion  being 
syphilitic,  nor  can  it  alone  serve  to  distinguish  accurately  a  meningeal  from  an 
ameningeal  nerve  lesion. 


186  THK    BIOLOGY,    CLINICAL    ASPECT   AND   TREATMENT   OF   SYPHILIS. 

Broadly  speaking,  the  higher  the  lymphocytosis,  the  greater  the  chance  that 
the  lesion  is  meningeal. 

Plasma  cells  and  embryo  Ijnnphocytes  are  occasionally  to  be  foimd  in  syphilitic 
degenerative  lesions. 

Endothelial  cells  are  often  to  be  found  in  syphilitic  meningeal  lesions. 

As  already  stated,  from  a  cytological  diagnosis  alone,  syphilis  must  not  be 
diagnosed,  unless  a  thorough  clinical  examination  has  excluded  all  other  causes. 

From  a  cytological  examination  alone,  it  is  almost  impossible  to  differentiate 
a  degenerative  from  a  meningeal  lesion  ;  but  weighed  in  the  balance  with  other 
points,  a  cell  count  is  a  very  helpful  factor  in  the  differentiation  of  the  two  conditions. 
A  h'mphocytosis  may  occur  very  early  in  syphilis,  even  before  a  positive  Wasser- 
mann  reaction  in  the  blood  is  obtained. 

The  fact  that  there  is  no  lymphoc3'tosis  in  the  cerebro-spinal  fluid  does  not 
exclude  latent  syphilis,  because  I  have  had  cases  in  the  latent  stage  of  the  disease 
which  had  a  normal  cerebro-spinal  fluid,  but  which  developed  a  degenerative 
encephalitis  later. 

A  case  of  degenerative  encephalitis  during  the  remission  period,  and  a  case  of 
quiescent  or  cured  degenerative  myelitis  may  have  a  normal  cerebro-spinal  fluid. 

In  many  cases  of  isolated  Argyll-Robertson  pupils,  the  cerebro-spinal  fluid  may 
be  normal.  This  is  an  important  point,  since  it  is  considered  that  a  patient  with 
Argyll-Robertson  pupils,  or  pupils  in  which  the  accommodation  reflex  has  vanished 
as  well,  is  sure  to  develop  a  degenerative  condition  later. 

Within  the  last  few  years  I  have  had  eleven  cases  of  pin  point  pupils,  which 
reacted  to  neither  light  nor  to  accommodation,  which  had  been  present  for  years, 
in  seven  of  which  the  cerebro-spinal  fluid  was  normal.  None  of  the  eleven  have, 
to  my  knowledge,  developed  a  widespread  degenerative  lesion.  I  do  not  think 
therefore,  if  a  patient  has  an  isolated  pupil  symptom  and  no  pathological 
changes  in  his  cerebro-spinal  fluid,  that  there  is  any  necessity  to  put  him  under 
treatment. 

In  many  cases  of  pure  arterial  lesions,  such  as  hemiplegia  and  paraplegia,  the 
cerebro-spinal  fluid  is  normal. 

The  interesting  question  which  now  arises  is.  What  is  the  origin  of  the  cells 
that  one  finds  in  the  cerebro-spinal  fluid  ?  At  present  there  are  two  opinions  : 
(1)  That  they  come  from  the  blood-vessels  ;  (2)  that  they  come  from  the  meninges. 
The  fact  that  more  cells  are  to  be  found  in  meningeal  than  in  arterial  lesions,  the  fact 
that  they  are  to  be  found  in  very  early  cases  of  syphilis  when  it  is  known  that  the 
meninges  are  infected,  the  fact  that  they  may  be  absent  in  such  conditions  as 
hemiplegia  and  paraplegia,  form  sufficient  proof  for  assuming  that  most  of  the 


EXAMINATION    OF   THE    CEREBRO-SPINAL    FLUID.  187 

cells,  at  auy  rate,  originate  from  the  meninges.  In  severe  meningeal  lesions,  endo- 
thelial cells  may  be  met  with,  and  it  is  in  endothelial  cells  that  lymphocytes  have 
origin.  Therefore,  instead  of  saying  that  lymphocytes  in  the  cerebro- spinal  fluid 
come  from  the  meninges,  it  would  be  more  correct  to  say  that  most  of  them 
originate  from  the  endothelial  cells  of  the  lymphatics  situated  in  the  meninges. 
The  reason  why  plasma  cells  and  embryo  lymphocytes  are  more  frequently  to  be 
found  in  the  late  parenchymatous  syphilitic  lesions  than  in  the  earlier  meningeal 
lesions,  is  doubtless  due  to  the  fact  that  the  protective  capacity  of  the  host  is 
strained  to  a  greater  action  in  the  former.  The  protective  ferment  action  of  a 
lymphocyte  is  increased  in  the  cell  to  which  it  gives  rise,  viz.,  the  plasma  cell,  hence 
the  presence  of  the  plasma  cell.  The  call  upon  the  lymphocyte  would  be  greater,  or 
better  to  say,  more  concentrated,  therefore  the  answer  would  be  not  so  much  an 
increase  in  the  number  of  lymphocytes ,  but  a  greater  call  upon  their  progenitors, 
viz.,  the  embryo  lymphocytes,  hence  the  explanation  of  their  presence.  These 
cells  probably  originate  from  the  lymphatics  of  the  nerve  tissue. 

The  influence  of  treatment  is  more  marked  upon  the  pleocytosis  than  upon  the 
protein  content,  or  upon  the  Wassermann  reaction.  Intravenous  injections  of 
salvarsan,  and  even  vigorous  treatment  with  mercurial  inunctions,  may  cause  a 
lymphocytosis  to  disappear,  that  is,  provided  the  lesion  is  a  meningeal  one.  The 
lymphocytosis  in  ameningeal  lesions  may  diminish,  as  the  result  of  treatment, 
especially  after  the  intrathecal  injections  of  salvarsanised  serum,  but  in  most  cases, 
it  ultimately  returns,  and  in  no  case  is  the  proportionate  disappearance  of  the  cells 
so  great  as  it  is  in  the  meningeal  lesions. 

Protein. 

The  next  important  step  is  to  examine  the  protein  content.  Neither  an  excess 
of  albumin  nor  of  globulin,  alone  proves  that  the  lesion  under  question  is  syphilitic. 

The  globulin  can  be  detected  by  an  opalescent  ring  which  forms  at  the  point  of 
contact,  when  a  saturated  solution  of  ammonium  sulphate  is  added  to  the  cerebro- 
spinal fluid.  This  ring  should  appear  within  three  minutes.  When  the  ring  has 
appeared,  the  tube  can  be  shaken,  when  the  whole  contents  become  opaque.  This 
constitutes  Nomie-Apelt's*  reaction,  phase  1. 

If  all  the  globulin  is  precipitated  by  ammonium  sulphate  and  separated  oflt, 
the  fluid  left  will,  if  albumin  is  present,  give  a  ring  with  nitric  acid — Heller's  test. 
This  constitutes  phase  2. 

The  globulin  is  also  precipitated  by  distilled  water,  partly  because  the 
electrolytes  which  are  attached  to  it  are  separated  ofl'.  If  a  single  drop  of  a  con- 
centrated solution  of  sodium  chloride  is  added,  the  opalescence  caused  by  the  distilled 


188  THE    BIOLOGY,    CLINICAL   ASPECT    AND    TREATMENT    OF   SYPHILIS. 

water   disappears.      The   globulin  also  gives  a  precipitate  with  acetic  acid  and 
potassium  ferrocyanide. 

Noguchis^  test. — This  test  depends  upon  the  precipitation  of  globulin  which 
occurs  when  butyric  acid  is  added  to  the  cerebro-spinal  fluid,  and  it  is  carried  out  as 
follows  : — 

To  0"1  c.c.  of  cerebro-spinal  fluid,  add  0"5  c.c.  of  a  10  per  cent,  solution  of 
butyric  acid  in  physiological  salt  solution  ;  boil  this  for  a  short  time,  and  quickly  add 
a  quantity  of  a  normal  solution  of  sodium  hydroxide  equal  to  the  amount  of  the 
cerebro-spinal  fluid  used.  Then  the  mixture  is  boiled  again  for  a  few  seconds. 
An  increase  of  protein  is  characterised  by  the  appearance  of  a  granular  or  flocculent 
precipitate.  If  the  amount  of  protein  is  very  small,  or,  in  other  words,  normal, 
the  precipitate  does  not  appear  until  after  standing  for  two  hours. 

Lange's  method.^ — This  is  also  called  the  CtoMsoI  reaction.  Globulin  has  the 
power  of  adsorbing,  and  thereby  precipitating  gold,  when  the  metal  is  in  a  colloidal 
condition.  The  protein  possesses  this  action  only  so  long  as  its  electrolytes  are 
still  attached  to  it,  hence,  when  this  test  is  used,  it  must  be  carried  out  as  soon  as 
possible  after  the  cerebro-spinal  fluid  has  been  withdrawn.  The  degree  of  j)re- 
cipitation  of  the  colloidal  gold  will  natural!}'  alter  the  colour  of  the  fluid  in  which 
it  was  suspended,  and  the  more  globulin  there  is,  the  more  gold  there  will  be  preci- 
pitated, hence  the  reaction  is  gauged  by  the  colour  of  the  solution. 

The  colloidal  gold  suspension  is  prepared  as  follows  : — In  a  1000  c.c.  flat- 
bottom  flask  of  best  Jena  glass  place  500  c.c.  of  distilled  water,  which  has  been 
freshly  prepared  in  vacuo  {vide  Chapter  XXVIII.).  Add  to  the  water  5  c.c.  of  a  2  per 
cent,  solution  of  potassium  carbonate,  and  almost  immediately  afterwards  add^5  c.c. 
of  a  1  per  cent,  solution  of  gold  chloride.  The  gold  chloride  must  be  chemically 
pm-e,  and  it  must  be  dissolved  in  protein  free  distilled  water.  Then  boil  the  contents 
of  the  flask  quickly,  just  until  bubbles  appear,  remove  the  flame  from  the  flask, 
add  3 '75  c.c.  of  a  1  per  cent,  solution  of  formaldehyde,  and  shake  well  until  the 
fluid  becomes  a  deep  cherry  red.  On  standing,  the  solution  should  become 
absolutely  clear  and  a  deep  red.  It  keeps  fairly  well,  but  it  is  wiser  to  use  only 
freshly  prepared  solutions.     The  reagent  may  be  called  the  Goldsol  indicator. 

In  order  to  perform  the  test,  obtain  a  test-tube  rack  holding  ten  test  tubes. 

Into  each  tube,  with  the  exception  of  the  first,  put  1  c.c.  of  a  0'4  per  cent, 
solution  of  sodium  chloride.  In  tube  No.  1  place  1'8  c.c.  of  the  salt  solution  and 
0'2  c.c.  of  the  cerebro-spinal  fluid,  mix  and  remove  1  c.c.  of  the  fluid.  Place  this 
in  tube  No.  2,  and  continue  the  procedure  until  each  tube  receives  a  gradually 
weaker  dilution  of  cerebro-spinal  fluid.  Now  add  to  each  tube  5  c.c.  of  the  Goldsol 
indicator,  and  mix  well.     Let  the  tubes  stand  for  twenty-four  hours  at    room 


EXAMINATION   OF   THE   CEREBRO-SPINAL   FLUID.  189 

temperature,  and  then  examine  them.     A  clear  sohition  indicates  a  positive  reaction. 
The  gradation  of  colours  is  from  an  absolutely  colourless  to  a  red  fluid. 

Kaplan's  method.' — In  a  test  tube  1  cm.  wide  and  8  cm.  long,  is  placed  0'5  c.c. 
of  cerebro-spinal  fluid.  It  is  twice  heated  up  to  boiling,  then  three  drops  of  a  5  per 
cent,  solution  of  butyric  acid  in  normal  saline  are  added,  followed  immediately  by 
0'5  c.c.  of  a  saturated  solution  of  ammonium  sidphate,  and  the  fluid  set  aside  for 
twenty  minutes.  In  adding  the  ammonium  sulphate  solution,  care  must  be  taken 
to  allow  it  to  flow  under  the  solution  and  not  to  mix  with  the  fluid  above  it. 

After  about,  twenty  minutes,  a  protein  excess  manifests  itself,  in  the  form  of  a 
thick  granular  ring.  "WTien  no  granular  ring  forms,  the  fluid  may  be  regarded  as 
normal.  Every  fluid  that  shows  tiie  ring  is  further  tested  as  to  the  intensity  of  the 
excess.  For  this  purpose,  four  other  tubes  receive  each  O'l,  0'2,  0'3,  and  0'4  c.c. 
of  cerebro-spinal  fluid  respectively,  and  each  in  turn  is  brought  up  to  the  0'5  c.c. 
mark  with  distilled  water.  The  same  procedure  is  then  followed  as  for  the  first 
tube.  The  quantity  of  protein  matter  permitting  a  ring  to  appear  in  the  tube 
containing  only  O'l  c.c.  of  spinal  flitid  is  designated  as  O'l  excess,  and  marks  the 
greatest  degree  of  increase. 

Zaloziecki^  recommends  the  Pandy  reaction,  which  he  performs  as  follows  : — 
From  80  to  100  c.c.  of  acidum  carbolicum  liquefactum  purissimum  are  brought  up 
to  1  litre  with  distilled  water.  The  mixture  is  shaken  thoroughly  and  placed  in  an 
incubator  for  a  few  hours.  After  complete  clarification  at  room  temperature, 
which  requires  several  days,  the  clear  supernatant  fluid  is  removed  and  used  as  the 
reagent.  A  drop  of  the  cerebro-spinal  fluid  is  permitted  to  trickle  down  the  side 
of  a  watch-glassful  of  the  reagent.  A  mild  reaction  is  characterised  by  the  appear- 
ance of  a  cloudiness  in  the  liquid  ;  a  strong  reaction  shows  a  white  precipitate. 
This  reaction  is  chiefly  produced  by  globulin,  but  may  also  be  obtained  with  albumin. 
In  cerebro-spinal  syphilis,  degenerative  myelitis,  and  degenerative  encephalitis, 
both  the  albumin  and  globxdin  are  increased,  but,  in  the  different  conditions,  the 
ratio  between  the  two  varies. 

In  cerebro-spinal  syphilis,  the  albumin  is  increased  more  than  is  the  case  in 
degenerative  myelitis  and  degenerative  encephalitis.  Therefore  a  meningeal  lesion 
can  easily  be  distinguished  from  an  ameningeal  lesion,  if  the  globulin  is  separated 
off  and  the  albumin  is  tested  quantitatively  with  nitric  acid. 

According  to  Bisgaard',  phase  2  is  practically  never  present  in  degenerative 
encephalitis  or  degenerative  myelitis,  if  the  cerebro-spinal  fluid  is  diluted  more 
than  1  in  20 ;  but  in  cases  of  meningitis,  whether  of  meningococcal,  tubercular,  or 
syphilitic  origin,  phase  2  may  be  positive  up  to  a  dilution  of  1  in  200. 

Oddly  enough,  very  little  attention  has  been  paid  to  the  albumin  content  of  the 


190  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT    OF    SYPHILIS. 

cerebro-spiiial  fluid,  coiisequeutl)^  I  should  like  to  make  a  few  observations  of  my 
own.  Whenever  the  pressure  is  increased,  there  always  appears  to  be  an  excess 
of  albumin.  Intravenous  injections  of  salvarsan  raise  the  albumin  content  con- 
siderably. Occasionally  a  cerebro-spinal  fluid  which  gave  a  ring  with  ammonium 
sulphate  will,  after  the  first  (and  much  less  frequently  after  the  second)  intrasjiinal 
injection  of  salvarsanised  serum,  fail  to  give  this  test,  but  in  such  instances  the 
albumin  content  is  usually  raised.  After  the  third  injection,  the  globulin  test 
becomes  positive  again,  and  the  albumin  content  duninishes.  I  cannot  help  thinking 
that  there  is  a  very  close  connection  existing  between  albumin  and  globulin — indeed, 
that  albumin  is  a  precursor  of  globulin,  as  it  is  practically  impossible  to  draw  a 
hard  and  fast  line  between  the  two,  and  to  tell  where  albumin  ends  and  globulin 
begins.  From  the  several  examinations  I  have  made,  I  am  sure  that  there  may  be 
a  trace  of  globulin  in  normal  cerebro-spinal  fluid.  When  the  central  nervous  system 
first  becomes  infected  in  syphilis,  the  albumin  content  increases,  then  the  globulin 
increases,  and,  as  time  goes  on,  the  more  the  globulin  increases,  the  less  the  albumin 
increases,  until  in  some  of  the  late  and  very  severe  cases,  the  albumin  content  may 
be  below  the  normal. 

Without  first  precipitating  the  globulin,  the  albumin  content  can  by  experience 
be  gauged  fairly  accurately,  by  a  naked  eye  examination  of  the  precipitate  caused 
by  the  addition  of  a  drop  or  two  of  a  saturated  solution  of  salicyl-sulphonic  acid. 
Naturally,  such  a  test  is  valueless,  when  the  globulin  content  is  raised.  If  the 
precipitate  caused  by  salicyl-sulphonic  acid  is  compared  side  by  side  with  that 
caused  by  the  addition  of  one  or  two  drops  of  a  5  per  cent,  solution  of  potassium 
ferrocyanide,  to  which  one  or  two  drops  of  a  30  per  cent,  solution  of  acetic  acid 
have  previously  been  added,  a  very  vahiable  test  is  obtained.  The  addition  of 
acetic  acid  and  potassium  ferrocyanide  precipitates  mainly  the  globulin,  and  is 
an  exceedingly  delicate  test.  Normal  cerebro-spinal  fluid  becomes  opaque  with 
salicyl-sulphonic  acid,  and  less  opaque  with  acetic  acid  and  potassium  ferrocyanide, 
but  the  dift'erence  is  slight.  As  the  albumin  is  increased,  the  opacity  of  the  s^alicyl- 
sulphonic  acid  tube  increases,  while  the  acetic  acid  and  potassium  ferrocyanide 
tube  remains  about  the  same  ;  anyhow,  the  difference  between  the  two  becomes 
very  marked.  If  the  opacity  in  the  salicyl-sulphonic  acid  tube  becomes  a  flocculent 
or  a  heavy  precipitate,  it  is  tolerably  certain  that  the  globulin  is  increased,  and 
that  it  will  give  a  ring  with  ammonium  sulphate. 

If  the  acetic  acid  and  potassium  ferrocyanide  tube  is  left,  it  gradually  assumes 
a  Berlin  blue  colour,  owing  to  the  reduction  that  has  taken  place. 

The  rapidity  with  which  this  Berlin  blue  colour  appears,  varies,  but  it  always 
appears  more  quickly,  the  more  globulin  that  is  present.     I  have  not  yet  fully 


EXAMIXATION   OF   THE    CEREBRO-SPIXAL    FLUID.  191 

worked  out  the  significance  of  the  reducing  action  of  the  cerebro-spinal  fluid,  but 
it  is  a  point  which  might  prove  of  vahie.  One  would  first  have  to  determine 
whether  the  increase  of  the  reducing  action  was  due  to  an  increase  of  the  normal 
reducing  substance,  in  the  cerebro-spinal  fluid,  or  to  an  increase  of  the  globulin, 
which  we  know  has  a  strong  reducing  action.  The  more  lipoid  that  is  attached 
to  the  globulin,  the  greater  its  reducing  action,  hence  the  reason  whj'  the  reducing 
action  is  more  marked  in  degenerative  than  in  non-degenerative  lesions. 

Two  tests  for  estimating  the  reducing  action,  are,  the  intensity  of  the  blue 
colour,  and  the  rapidity  with  which  it  is  produced  by  the  addition  of  a  drop  or  two 
of  an  alcoholic  solution  of  alkali  blue  which  has  been  decolourised  with  potassium 
hydrate  ;  the  intensity  and  rate  of  production  of  colour,  when  a  piece  of  gold 
chloride  paper  is  left  in  the  fluid. 

The  reducing  action  may  also  be  tested  for  with  Fehling's  reagent. 

The  reader  will  be  aware  that,  a  few  lines  back,  I  drew  attention  to  the  fact  that 
the  globulin  test  might  fail,  after  the  first  or  second  injection  of  salvarsanised  serum. 
By  the  unwary,  this  is  assumed  as  showing  that  one  or  two  injections  have  cured 
the  patient.  Not  only  ma}^  the  globulin  disappear,  but  the  Wassermann  reaction 
may  become  negative.  Exactly  the  same  thing  may  happen  with  the  serum  from 
a  late  case  of  syphilis  (vide  Chapter  XI). 

The  decrease  in  globulin  and  the  negative  Wassermann  reaction  is  smiply  due 
to  the  fact,  that  the  existing  lipoid-globulin  particles  become  hydrolysed,  when 
salvarsan  or  salvarsanised  serum  is  first  given.  This  is  the  explanation  of  the 
so-called  negative  phase.  Improvement  only  follows  when  the  negative  phase  has 
passed  off,  and  this  is  due  to  the  destruction  of  the  old  lipoid-globulin  particles,  and 
to  the  formation  of  new  ones.  It  is,  moreover,  an  indication  for  further  treatment, 
not  for  a  stoppage  of  the  same. 

The  excess  of  protein  in  the  cerebro-spinal  fluid  probably  comes  from  three 
sources  :   (1)  leucocytes  ;   (2)  epithelial  cells  of  the  choroid  plexus  ;   (.3)  nerve  cells. 

The  reason  why  more  globulin  is  found  in  degenerative  lesions,  is  doubtless 
due  to  the  fact  that  some  of  the  lymphocytes  have  formed  plasma  cells,  the  proto- 
plasm of  which  is  richer  in  globulin,  because  the  cells  of  the  choroid  plexus  and 
nerve  cells  are  more  involved,  and  both  are  rich  in  lipoid-globulin  adsorption  com- 
plexes. From  what  has  been  said,  one  would  expect  to  find,  in  some  of  the 
degenerative  cases,  that  the  globulin  in  the  cerebro-spinal  fluid  existed  in  the  form 
of  lipoid-globulin,  which  happens  to  be  the  case,  and  what  has  just  been  called 
globulin  in  degenerative  lesions  is  probably  more  often  lipoid-globulin,  than  pure 
serum-globulin.     Here  again  there  is  no  clear  line  of  demarcation  between  the  two. 

The  larger  the  amount  of  lipoid  which  is  attached  to  the  globulin,  the  stronger 

N 


192  THE   BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   SYPHILIS. 

is  the  oxydase  reaction  of  the  cerebro-spinal  fluid.  Now,  the  oxydase  reaction  is 
practically  always  present  in  ameningeal  lesions,  and  not  in  meningeal  lesions,  which 
is  strong  proof  of  my  assumption,  that  lipoid-globulins  are  more  abundant  in  the 
cerebro-spinal  fluid  from  cases  of  degenerative  encephalitis,  than  from  cases  of 
cerebro-spinal  meningitis. 

According  to  Bisgaard,*  the  total  nitrogen  in  normal  cerebro-spinal  fluid  varies 
from  O'OIO  to  0"025  per  cent.,  while  in  degenerative  encephalitis  it  varies  from 
0'0144  to  0"0345  per  cent.  Cases  of  Tumor  cerebri,  Abscessus  cerebri,  and  juvenile 
degenerative  encephalitis  show  the  same  nitrogen  content  as  ordinary  degenerative 
encephalitis.  The  same  may  be  said  of  degenerative  myelitis  and  disseminated 
sclerosis.     Lues  cerebri,  on  the  other  hand,  shows  a  higher  N-value. 

Acute  meningitis,  of  whatever  origin,  shows  the  highest  N-value,  as  the  following 
three  cases  from  Bisgaard's®  table  prove  : — 

Lues  cerebro-spinalis     . .         . .         . .         . .         . .     0 "  0582  per  cent. 

Streptococcal  meningitis  ..         ..         ..         ..     0'2260        ,, 

Tubercular  meningitis  . .         . .         . .         . .         . .     0'  1164        ,, 

The  acuter  the  meningitis,  the  higher  the  N-value,  and  the  greater  the  ratio 
of  the  albumin  to  the  globulin ;  therefore,  the  chief  excess  of  the  N  comes  from  the 
albumin,  and  not  from  the  globulin.  During  the  agony  of  death,  and  for  some 
time  after,  Bisgaard  found  that  the  N-value  of  the  cerebro-spinal  fluid  was  very 
much  increased,  but  that  the  excess  was  mainly  non-protein  nitrogen. 

The  Wassermann  reaction  is  enormously  increased  in  the  cerebro-spinal  fluid 
just  before  death  and  for  some  time  afterwards — in  fact,  a  positive  reaction  may  be 
obtained  with  a  fluid  which  was,  during  life,  normal. 

The  lipoids  are  very  much  increased  in  the  cerebro-spinal  fluid  under  the  above 
conditions. 

As  I  have  shown  that  a  ratio  exists  between  the  amount  of  lipoid  ^-idiich  is 
attached  to  the  globulin  and  the  strength  of  the  Wassermann  reaction,  it  is  highly 
probable  that  this  non-protein  nitrogen  conies  from  nitrogen  containing  phosphatids 
which  displace  the  NH,  groups  of  the  protein  molecule,  and  thereby  cause  a  positive 
Wassermann  reaction. 

Therefore  some  relationship  exists  between  the  N-value  and  the  Wassermann 
reaction. 

This  interesting  part  of  my  work  is  discussed  more  fully,  in  the  chapter 
dealing  with  the  Wassermann  reaction  (Chapter  X). 

The  influence  of  treatment  upon  the  protein  content  of  the  cerebro-spinal  fluid 
is    variable.      Broadly   speaking,    in   meningeal   lesions,   when  salvarsan  is  given 


EXAMINATION   OF   THE   CEREBRO-SPINAL    FLUID.  19:3 

intravenously  and  intrathecally,  the  pathological  excess  may  be  made  to  disappear. 
In  ameningeal  lesions,  although  treatment  may  cause  a  diminution  in  the  amount 
of  globulin,  it  practically  never  results  in  causing  its  entire  removal. 

At  present,  no  great  importance  attaches  to  the  fact  that,  in  syphilitic  lesions  of 
the  central  nervous  system,  the  pressure  of  the  cerebro-spinal  fluid  is  often  raised. 
The  only  other  test  which  need  be  considered  is  the  AVassermann  reaction. 

Wassermann  Reaction. 

A\Tiile  the  Wassermann  reaction  mil  tell  you  that  the  condition  under 
question  is  certainly  syphilitic,  and  no  other  test  will  do  this,  it  will  not  help  alone 
in  differentiating  the  various  syphilitic  lesions.  Hence  the  reason  why,  when  the 
cerebro-spinal  fluid  is  examined,  several  tests  are  used.  As  a  matter  of  fact,  in 
practically  every  case,  all  we  want  to  know  is  whether  the  condition  is  syphilitic 
or  not,  and  this  can  only  be  answered  by  the  Wassermann  reaction.  As  to 
whether  the  condition  is  a  degenerative  one  or  not,  can  practically  only  be  settled 
in  difficult  cases  by  the  action  of  treatment. 

An  important  point  to  remember  is,  that  a  Wassennann  reaction  in  the 
cerebro-spinal  fluid  should  never  be  returned  as  negative,  until  the  fluid  has  been 
used  in  the  strength  of  1,000  percent,  {i.e.,  1  c.c.  instead  of  1/lOth  c.c.  of  a  1  in  10 
dilution).  Since  the  complement  fixing  capacity  of  the  cerebro-spinal  fluid  is 
practically  nil,  a  1,000  per  cent,  strength  can  be  used  without  risk. 

Wassermann^"  has  recently  shown  that  the  reagin,  i.e.,  the  reacting  substance 
of  the  cerebro-spinal  fluid,  comes  from  the  Ipnphocytcs. 

This  can  be  only  partly  true,  since  treatment  may  cause  the  lymphocytosis  to 
vanish,  and  yet  the  positive  Wassermann  reaction  will  remain  so. 

Again,  the  Wassermann  reaction  is  most  positive  in  parenchymatous  lesions, 
while  the  Ipnphocytosis  is  greatest  in  the  meningeal  lesions. 

The  Wassermann  reaction  may  be  increased  post-mortem,  without  there 
being  a  corresponding  increase  in  the  number  of  lymphocytes. 

The  Wassermann  reaction  is  increased  when  the  nitrogen-containing  phos- 
phatids  are  increased  ;  when  there  is  the  greatest  change  in  the  cells  of  the  choroid 
plexus,  which  are  rich  in  N-containing  phosphatids  ;  when  there  is  the  greatest 
destruction  of  Nissl's  granules,  which  contain  N-containing  phosphatids. 

Therefore,  although  the  reagin  does  partly  come  from  the  lymphoc3rtes,  it  also 
comes  from  the  choroid  plexus  and  nerve  cells. 

The  reagin  in  the  blood  cannot  get  into  the  cerebro-spinal  fluid,  but  the  reverse 
can  happen,  as  the  following  case  shows  : — 

Case  25. — A  patient  consulted  me  once  a  year  for  three  years.     On  these  three 

n2 


194  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

occasions,  I  coiild  find  no  signs  of  syphilis,  and  the  Wassermann  reaction  was 
invariably  negative.  A  few  months  after  the  last  visit,  symptoms  of  degenerative 
encephalitis  set  in.  The  diagnosis  was  confirmed  by  an  examination  of  the  cerebro- 
spinal fluid,  and  at  the  same  time  the  AVassermann  reaction  in  the  blood  was  strongly 
positive. 

Since  then,  I  have  been  able  to  confirm  this  point  in  otber  cases,  and  it  may 
occur  in  any  degenerative  lesion,  but  it  is  more  likely  to  occur  in  degenerative 
encephalitis  than  in  degenerative  myelitis. 

It  would  be  as  well  now  to  discuss  the  value  of  the  cerebro-spinal  fluid  finding, 
compared  with  the  clinical  condition,  because  an  examination  of  the  cerebro-spinal 
fluid  will  assist  in  differentiating  a  meningeal  from  an  ameningeal  lesion,  or  a 
degenerative  from  a  non-degenerative  lesion. 

The  clinical  conditions  will  be  mentioned  in  the  order  in  which  they  appear 
in  the  table  in  Chapter  XXIII. 

Brain. 
Meningeal. 

Pachymeningitis  and  Leptomeningitis. — Protein  excess,  but  the  excess  is  mainlj- 
albumin,  although  -the  globulin  is  increased  as  well.  The  cell  count  is  high,  and 
mainly  consists  of  lymphocji^es,  polymorj)honuclear  leucocytes,  and  endothelial 
cells.  The  Wassermann  reaction  is  present  in  the  high  percentage  solutions  only. 
The  Wassermann  reaction  in  the  blood  is  not  infrequently  negative. 

Meningo-encephalitis. — Protein  excess,  but  the  excess  is  mainly  globulin, 
although  the  albumin  is  increased  as  well.  The  ratio  between  the  albumin  and 
globulin  will  depend  upon  how  meningeal  or  how  encephalitic  the  process  is.  The 
cell  count  is  not  so  high  as  the  process  becomes  more  encephalitic,  but  the  ratio 
between  the  lymphocytes  and  polymorphonuclear  leucocytes  is  altered,  owing  to 
the  fact  that  the  excess  of  the  former  is  maintained,  while  the  latter  are  diminished. 

The  absence  of  endothelial  cells  points  to  an  involvement  of  nerve  tissue.  The 
Wassermann  reaction  is  positive  in  weaker  dilutions  of  the  cerebro-spinal  fluid, 
and  the  same  ratio  does  not  exist  between  the  negativity  of  the  blood  and  the 
positivity  of  the  cerebro-spinal  fluid.  In  other  words,  when  nerve  tissue  becomes 
involved,  the  positive  Wassermann  reaction  in  the  blood  tends  to  reappear. 

Degenerative  encephalitis. — Protein  excess,  but  of  the  globulin  only  ;  the  albumin 
may  be  diminished.  The  globulin  maj-  be  a  lipoid-globulin,  hence  the  oxydase 
reaction  is  often  present.  The  oxydase  reaction  (amino-acidases)  can  be  tested 
by  adding  solutions  of  the  amino-acids  to  the  cerebro-spinal  fluid,  incubating  over 


EXAMINATION   OF   THE   CEREBRO-SPINAL    FLUID.  195 

night,  and  noting  the  changes  in  colour,  next  morning.  The  cell  content  is  increased, 
but  not  to  a  marked  degree,  the  cells  are  mainly  lymphocytes,  but  plasma  cells 
and  embryo  lymphocytes  may  be  met  with.  The  Wassermann  reaction  is,  as  a 
rule,  positive  in  all  dilutions,  and  the  Wassermann  reaction  of  the  blood,  too,  is 
almost  invariably  positive. 

Ameningeal. 

Pure  arterial  lesions,  without  involvement  of  nerve  substance. — The  cerebro- 
spinal fluid  is  generally  normal. 

Arterial  lesions,  ivith  involvement  of  nerve  substance. — If  the  nerve  substance 
is  involved  mechanically,  as  happens  in  a  haemorrhage  from  a  late  arterio-sclerotic 
lesion,  the  cerebro-spinal  fluid  is,  as  a  rule,  normal. 

In  most  cases  of  gummata,  the  pathological  changes  are  what  one  might  call 
borderline  changes,  i.e.,  the  cell  count  may  be  12  or  15  per  c.mm.,  doubt  exists  as 
to  whether  there  is  a  protein  excess  or  not.  The  Wassermann  reaction  in  the 
blood  is  generally  positive,  and  it  may  or  may  not  be  positive  in  the  cerebro-spinal 
fluid.  It  often  happens  that  the  cerebro-spinal  fluid  is  normal,  in  cases  of  Gumma 
cerebri. 

In  cases  of  degenerative  encephalitis,  at  first  there  may  be  practically  no 
changes  ;  then  occurs  a  protein  excess  which  is  mainly  globulin.  The  cell  count  is  never 
high ;  often  it  does  not  exceed  25  cells  per  c.mm.,  and  then  consists  almost  invariably 
of  lymphocytes  only.  The  oxydase  reaction  is  generally  negative,  and  so  may 
the  Wassermann  reaction  be.  Even  in  advanced  cases,  the  Wassermann  reaction 
may  only  be  positive  when  high  percentage  solutions  are  used.  In  the  blood,  the 
Wassermann  reaction  is  often  negative,  at  any  rate  in  the  early  stage  of  the  trouble. 
The  pathological  changes  may  easily  disappear  under  intrathecal  injections  of 
salvarsanised  serum,  in  spite  of  which  the  patient  rapidly  becomes  demented  and 
dies.  In  the  other  form  of  degenerative  encephalitis,  the  pathological  changes 
are  not  readily  influenced  by  intrathecal  injections,  although  the  clinical  condition 
may  improve.  Therefore,  an  examination  of  the  cerebro-spinal  fluid  ^"ill  often 
help  one  to  differentiate  a  degenerative  encephalitis  of  meningeal  origin  from  a 
case  of  ameningeal  origin. 

Cord. 

What  I  have  said  about  the  brain,  applies  equally  well  to  the  cord,  therefore 
recapitulation  is  unnecessary,  but  there  are  one  or  two  differences  which  require 
special  mention. 


196  THE    BIOLOGY,    CLINICAL    ASPECT   AND   TREATMENT   OF    SYPHILIS. 

In  cases  of  degenerative  n\yelitis  of  meningeal  origin,  the  oxydase  reaction  is 
not  present  so  often  as  it  is  in  cases  of  degenerative  encephalitis,  and  it  is  never 
very  marked,  when  it  is  present.  Furthermore,  this  form  of  degenerative  myelitis 
has  not  the  same  influence  in  causing  a  positive  Wassermann  reaction  in  the  blood 
as  its  intracranial  cogener  has,  and,  speaking  generally,  the  Wassermann  reaction 
is  not  so  often  positive  in  the  cerebro-spinal  fluid.  A^'hen  a  more  or  less  normal 
cerebro-spinal  fluid  is  found  in  a  case  of  degenerative  encephalitis  or  myelitis,  the 
observer  nmst  always  ask  himself,  whether  he  is  dealing  with  a  patient  in  the 
quiescent  stage,  in  the  former  ;  or  with  a  patient  whose  process  has  undergone  a 
spontaneous  cure,  in  the  latter. 

Spontaneous  cure  of  degenerative  encephalitis  probably  does  not  exist,  while 
spontaneous  cure  of  degenerative  myelitis  occurs  in  quite  a  high  percentage  of  cases, 
and  this  is  doubtless  one  of  the  reasons,  why  so  many  observers  state  that  the 
Wassermann  reaction  is  not  so  constantly  positive  in  the  cerebro-spinal  fluid, 
in  cases  of  degenerative  myelitis,  as  it  is  in  cases  of  degenerative  encephalitis. 
Spontaneous  cure  of  degenerative  m^^elitis  is  usually  overlooked,  for  the  simple 
reason  that  the  clinical  signs  and  symptoms  of  the  lesion  persist — it  is  forgotten 
for  the  time  being  that  nerve  tissue  does  not  regenerate  ;  therefore  once  damaged, 
always  damaged. 

An  extremely  interesting  and  useful  point,  which  a  pathological  examination 
of  the  cerebro-spinal  fluid  reveals,  is  the  persistence  of  a  positive  Wassermann 
reaction,  in  spite  of  the  most  drastic  and  prolonged  treatment. 

In  such  cases,  one  can  tell  that  the  patient  has  a  degenerative  lesion  of 
meningeal  origin.  It  does  not  mean  that  there  are  actually  organisms  present, 
or  that  the  disease  is  progressive,  or  even  active.  This  persistent  Wassermann 
reaction  may  be  due  to  the  chemical  products  which  emanate  from  the  disintegration 
of  nerve  cell,  and  fibres,  or  it  may  be  due  to  that  continued  production  of  anti- 
bodies, to  which  the  cells  give  rise,  in  spite  of  the  fact  that  there  are  no  more 
organisms  to  attack.  This  persistent  production  of  antibodies  is  very  commonly 
seen  in  the  systemic  portion,  and  it  accounts  for  the  Wassermann-fast  reactions 
which  may  be  obtained  in  patients,  who  are  in  the  best  of  health  and  show  no 
symptoms. 

Kaplan's'  goldsol  curves  will  materially  assist  one  in  making  a  diagnosis  of 
a  degenerative  lesion.  The  colour  of  the  gold  solution,  as  has  already  been 
mentioned,  is  a  deep  red,  and  as  it  is  absolutely  necessary  that  it  should  be  of  no 
other  colour,  it  is  a  very  good  plan  to  control  it.  The  best  way  to  control  the  colour 
is  as  follows : — In  an  ordinary  |-inch  test  tube  place  15  c.c.  of  a  decinormal  sodium 
hydroxide  solution;    add  0'2  c.c.  of  a  0'5  jier  cent,  solution  of  Congo  red    and 


EXAMINATION   OF   THE    CEREBRO-SPINAL   FLUID. 


197 


0'3  c.c.  of  a  1  per  cent,  solution  of  alizarin.  The  intensity  and  nuance  of  the  colour 
in  the  test-tube,  as  viewed  by  transmitted  light,  correspond  exactly  with  the  depth 
and  colour  of  the  indicator  in  the  flask,  viewed  in  a  similar  way.  Kaplan  sets  up 
a  set  of  9  to  12  tubes  containing  dilutions  of  cerebro-spinal  fluid  from  1  :  10  to 
1  :  2560.  The  goldsol  is  placed  in  each  tube,  and  is  permitted  to  remain  at  room 
temperature  over  night.  The  next  morning,  some  tubes  will  show  definite  colour 
changes,  which  he  designates  as  follows  : — 


Complete  precipitation,  Huid  colourless 

The  slightest  tinge  of  steel-grey 

Deeper  grey  to  blue 

A  reddish-blue  or  bluish-red    ... 

A  red  colour  slightly  different  from  the  original  colour 

No  change  in  colour 


4 
3 
2 

1 

0 


The  numbers  are  arranged  from  5  down  to  0  ;   the  dilutions  are  arranged  from 
left  to  right,  beginning  with  the  1  :  10  tube : — 


3 
2 
1 

0 

o    o    o 

o    o    o    00    o    0-1 

r-<      <M       ^       00       i-^       CC       C^       ^      Ol       O 


The  curve  obtained  from  patients  with  degenerative  encephalitis  is  usually 
like  this : — 


o    o    o 

o    c    o    X    o    rtJ 


This  means  that  there  was  no  colour  in  the  first  three  tubes,  and  in  the   rest 
the  colour  was  normal. 


198  THE   BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   SYPHILIS. 

The  curve  of  eerebro-spinal  syphilis  is,  according  to  Kaplan,  like  this : 


O  O  00  CO  c-j 
Gq  -t  CM  lO  r-t 
70      :0      r-H      (M      o 


The  goldsol  reaction  has  not  been  sufSciently  long  in  use  for  anyone's  experience 
with  it  to  be  great  enough  to  allow  of  his  making  authoritative  statements  about 
it.  That  it  is  a  useful  test  cannot  be  denied,  and  it  does  undoubtedly  aid  one  in 
differentiating  a  degenerative  from  a  non-degenerative  lesion. 

Broadly  speaking,  in  cases  of  degenerative  encephalitis  and  myelitis,  the  first 
one,  two  or  three  tubes  show  complete  precipitation  of  colloidal  gold,  and  the  rest 
are  normal,  while  in  non-degenerative  aii'ections  the  curve  is  irregular. 

In  order  to  enable  the  physician  at  a  glance  to  tell  whether  he  is  dealing  with 
a  degenerative  or  a  non-degenerative  lesion,  I  append  the  following  table  : — 


Degenerative. 

Globulin  increased  out  of  proportion  to  the 
albumin.     May  be  a  diminution  of  albumin. 

Cell  count  nearly  always  less  than  100  cells 
per  c.mm. 

Cells  are  lymphocytes,  plasma  cells,  and 
embryo  lymphocytes. 

Oxydase  reaction  may  be  present. 

"Step-ladder"  Goldsol  curve  obtained  in 
over  90  per  cent,  of  cases. 

Wassermann  reaction  almost  always 
positive  in  blood. 

Wassermann  reaction  almost  always 
positive  in  eerebro-spinal  fluid,  even  when 
only  a  weak  dilution  of  fluid  is  used. 

Reducint;  action  demonstrable  at  once. 


Non-degenerative. 

Albumin  increased  more  than  the  globulin. 
In  about  50  per  cent,  of  cases  there  is  an 
excess  of  globulin. 

Cell  count  usually  more  than  100  cells  per 
c.mm. 

Cells  are  lymphocytes,  polymorphonuclear 
leucocytes,  and  endothelial  cells. 

Oxydase  reaction  not  present. 

Curve  if  present  is  irregular,  and  it  i?  often 
absent. 

\Yassermann  reaction  frequently  absent  in 
blood. 

Wassermann  reaction  only  positive  in 
eerebro-spinal  fluid,  when  strong  dilutions  of 
fluid  are  used. 

Reducing  action  usually  delayed,  or  may 
even  be  absent. 


EXAMINATION    OF   THE    CEREBRO-SPINAL   FLUID.  199 

'  Xonne  (1909),  "  Syphilis  u.  Nervensystem,"  2'"  Auflage.     S.  Karger.     Berlin. 

-  Nonne  (1913),  "  Syphilis  and  the  Nervous  System,"  translat.  by  Ball.  J.  B.  Lippincott. 
Philadelphia. 

'  Fuchs  u.  Rosenthal  (1904),  "  Wien.  nied.  Presse,"  xlv,  2081. 

'  Xonne  u.  Apelt  (1907),  "  Arch.  f.  Psych,  u.  Nervenheilkunde,"  xliii,  4.33. 

'  Xognchi  (1909),  "  Proc.  Soc.  for  Exper.  Biol.  Med.,"  vi,  51. 

"  Lange  (1912),  "  Zeitschr.  f.  Chemotherapie,"  i,  44. 

'  Kaplan  (1914),  "  Serology  of  Nervoiis  and  Mental  Diseases."  W.  B.  Saiuiders.  Phila- 
delphia. 

s  Zaloziecki  (1913),  "  Deutsch.  Zeitschr.  f.  Nervenheilkunde,"  sivii-xlviii,  783. 

"  Bisgaard  (1914),   "  Biocheraische  Zeitschr.,"  Iviii,   1. 

' »  Wassermann  u.  Lange  (1914),  "  Berl.  klin.  Woch.,"  li,  i,  527. 


WORKS   CONSULTED. 

Alzheimer  (1907),  "  Centr.  f.  Nervenh.  u.  Psy.,"  sxx,  449. 

Blumenthal  (1902),  "  Ergebnisse  der  Phys.,"  i,  285. 

Boas  (1911),  "Die  Wassermannsche  Reaction."     Karger.     Beriin. 

Bruch  (1909),  "Die  Serodiagnose  der  Syphilis."     J.  Springer.     Berlin. 

Candler  (1911),  "Lancet,"  ii,  1320. 

Dreyfus  (1912),  "  Munch,  med.  Woch.,"  lix,  1C47. 

Ellis  and  Swift  (1913),  "  Journ.  Exp.  Med.,"  xviii,  162. 

Hough  (1910),  "Bull.  No.  2  Gov.  Hosp.  for  Insane,"  Washington,  p.  118. 

Hauptmann  (1911),  "  Deut.  Zeitschr.  f.  Nervenheilkunde,"  slii,  240. 

Jones  (1909),  "American  Journ.  of  Insanity,"  Ixv,  653. 

Kafka  (1912),  "  Neurol.  Centralbl.,"  xxxi,  627,  923. 

Kafka  (1911),  "  Zeitschr.  f.  d.  ges.  Neurol,  u.  Psych.,"  iv,  117. 

Mott  (1910),  "  Lancet,"  ii,  179. 

Mott  (1909),  "  Arch,  of  Neurol,  and  Psjch.,"  iv,  13. 

Pandy  (1910),  "Neurol.  Centralbl.,"  xxix,  915. 

Pighini  (1912),  "  Biochem.  Zeitschr.,"  xhi.  129. 

Plant   (1909),    "Die   Wassermannsche   Serodiagnostik   der  Syphilis    in  ihrer  Anwendung 

auf  die  Psychiatre."     G.  Fischer.     Jena. 
Ross  and  Jones  (1909),  "  Brit.  Med.  Journ.,  i,  1111. 
Ravaut,  Gastinel  et  Velter  (1910),  "  La  rachicentese."     Masson.     Paris. 
Szesci  (1911),  "Monats.  f.  Psych,  u.  Neurol.,"  xxix,  76. 


CHAPTER  XXIir. 
THE  BIOLOGY  OF  SYPHILIS  OF  THE  NERVOUS  SYSTEM. 

In  this  chapter,  I  propose  to  discuss  the  following  points : — {a)  The  stage  in 
syphilis  at  which  the  nervous  system  becomes  involved ;  (6)  the  paths  and  sites  of 
infection  of  the  syphilitic  lesions  of  the  central  nervous  system  ;  (c)  the  influence 
which  treatment  has  upon  the  incidence  of  syphilitic  nervous  lesions ;  (d)  other 
factors  which  play  a  role  in  the  causation  of  syphilitic  nervous  lesions. 

(a)  The  Stage  in  Syphilis  at  which  the  Nervous  System  becomes  Involved. 

It  is  very  generally  assumed  that  infection  of  the  central  nervous  system,  by 
the  organism  which  is  the  cause  of  syphilis,  takes  place  at  a  late  stage  of  the  disease. 

This  assumption  has  probably  been  made,  because  of  the  known  clinical  fact 
that  nervous  lesions  appear  in  the  so-called  tertiary  stage  of  the  disease,  frequently 
at  a  considerable  interval  (sometimes  many  years)  after  the  primary  infection. 
There  is,  however,  no  doubt  that  infection  of  the  central  nervous  system,  including 
the  blood-vessels  and  meninges,  may  occur  at  an  early  stage  of  the  disease,  and 
personal  observations,  which  will  be  considered  here,  incline  me  to  believe  that 
every  syphilitic  nerve  lesion  arises  directly  from  the  presence  of  the  organism,  which 
reached  the  nervous  system  during  the  stage  of  general  infection. 

From  my  own  researches,  I  have  no  doubt  that  the  leucocytozoon  reaches  the 
central  nervous  system  during  the  stage  of  generalisation  only,  and  that,  in  from 
60  to  70  per  cent,  of  all  cases  of  sj'philis,  it  is,  moreover,  the  direct  cause  of  the 
syphilitic  nervous  lesions.  By  this  last  statement,  I  mean  that  every  nerve  lesion  is 
due  to  the  presence  of  the  organism  itself,  and  not  to  its  toxine  alone. 

It  is  not  in  every  case  of  syphilis  that  the  organism  becomes  generalised, 
because,  as  I  have  already  explained,  the  Leucocytozoon  syjiliilidis  may  develop 
aberrantly,  that  is  to  say,  only  the  asexual  stage  may  be  perfected,  or  the  organism 
may  develop  by  parthenogenesis.  When  the  organism  develops  abnormally,  the 
disease  remains  more  or  less  localised  to  the  site  of  infection.     Naturally,  in  these 


THE    BIOLOGY   OF    SYPHILIS   OF   THE    NERVOUS    SYSTEM.  201 

cases,  the  nervous  system  is  spared.  Every  clinician  is  fully  aware  that,  so  far  as 
the  systemic  portion  of  the  body  is  concerned,  i.e.,  in  contradistinction  to  the 
nervous  portion,  the  patient  may  develop  no  signs  or  symptoms  during  the  genera- 
lisation stage,  and  that,  in  a  few  cases,  the  Wassermann  reaction  maj'  even  be 
negative  throughout  the  early  part  of  this  period.  The  same  may  happen  in  the 
nervous  portion.  Organisms  naa}-  reach  the  nervous  system,  and  not  give  rise  to 
signs  or  symptoms,  and  the  cerebro-spinal  fluid  may  show  no  pathological  change. 

Therefore,  when  one  states  that  there  is  evidence  that  the  sj'jjhilitic  organism 
invades  the  central  nervous  system  in  from  60  t»  70  per  cent,  of  all  cases  of  syphilis, 
it  does  not  mean  that  in  30  per  cent,  of  cases  it  remains  free. 

Many  nervous  lesions,  as  we  know,  are  purely  arterial  in  origin,  ride  hemi- 
plegia and  transverse  myelitis.  Now,  pure  arterial  lesions  of  the  nervous  system, 
anyhow  in  the  early  part  of  their  career,  produce  no  pathological  changes  in  the 
cerebro-spinal  fluid. 

The  parts  of  the  nervous  system  first  involved  are  the  meninges  and  the  blood 
vessels.  It  has  just  been  shown  that  an  involvement  of  the  blood-vessels  cannot 
be  detected  beforehand,  therefore,  it  is  only  when  the  meninges  are  infected,  that 
we  can  be  sure  that  the  organisms  have  reached  the  nervous  system. 

Unless  a  sufiicient  number  of  organisms  reach  the  meninges,  and  unless  they 
produce  actual  inflammation  in  the  meninges,  the  latter  being  analogous  to  the  rash 
in  the  systemic  portion,  it  will  naturally  follow  that  there  will  be  no  signs  or 
symptoms  of  a  nervous  infection,  and  the  cerebro-spinal  fluid  will  be  normal.  From 
this,  the  reader  will  see  that,  because  in  30  to  40  per  cent,  of  all  cases  of  syphilis  no 
sign  or  symptom  of  a  nervous  infection  is  ascertainable,  it  is  no  proof  that  the 
organism  has  not  invaded  the  nervous  system. 

AVhen  it  is  stated  that,  in  60  to  70  per  cent,  of  all  cases  of  syphilis,  the  Leuco- 
cytozoon  syphilidis  reaches  the  nervous  system,  it  means  that,  in  60  to  70  per  cent, 
of  all  cases  of  early  generalised  syphilis,  either  the  patient  has  signs  or  symptoms 
of  a  meningitis,  or  pathological  changes  are  to  be  found  in  the  cerebro-spinal  fluid. 
These  are  the  figures  I  have  arrived  at  from  a  careful  examination  of  a  very  large 
number  of  cases.  Only  those  cases  have  been  considered  which  were  in  the 
generalisation  stage,  and  in  which  no  treatment  had  been  prescribed. 

The  reader  might  now  say  to  himself,  what  proof  is  there  that,  in  the  30  to 
40  per  cent,  of  cases  in  which  there  is  no  sign  or  symptom  of  a  syphilitic  invasion 
in  the  generalisation  stage,  the  organisms  do  not  reach  the  nervous  system 
at  a  later  date.  The  proof  that  the  nervous  system  is  invaded  at  about  the  same 
time  as  the  systemic  portion  of  the  body,  and  that  any  late  lesion  which  arises  dates 
from  this  invasion,  and  from  this  invasion  only,  is  forthcoming  in  the  study  of  the 


202  THE   BIOLOGY,    CLINICAL    ASPECT   AND   TREATMENT   OF   SYPHILIS. 

relationship  which  exists  between  the  first  maculo-papular  rash  and  the  recurrent 
papular  lesions  and  gunimata.  Furthermore,  and  this  fact  proves  my  point, 
in  many  of  these  30  to  40  per  cent,  of  cases,  signs  and  symptoms  of  nervous  lesions 
make  their  iii'st  appearance  when  the  salvarsan  treatment  is  stopped,  and,  in  many, 
it  is  only  then  that  pathological  changes  in  the  cerebro-spinal  fluid  are  to  be  found. 
Salvarsan  sterilises  the  systemic  portion  of  the  body,  but  not  the  nervous  portion, 
therefore  it  would  be  impossible  for  an  invasion  to  take  place  from  an  area  in  which 
there  were  no  organisms.  The  reason  why  signs  and  symptoms  make  their  first 
appearance  after  treatment  is  fully  considered  below. 

From  what  has  been  stated,  it  may  be  reasonably  assumed  that,  broadly 
speaking,  the  nervous  portion  is  invaded  by  the  syphilitic  organism  as  often 
as  is  the  systemic  portion.  This  may  not  be  absolutely  true,  but  if  the  chances  of 
the  nervous  portion  being  infected  are  considered  to  be  as  great  as  those  of  the 
systemic  portion,  it  will  make  the  physician  much  more  careful.  It  ^vill  make  the 
phj'sician  take  more  pains  to  examine  thoroughly  every  early  case  of  syphilis ;  it 
will  also  make  him  cautious  as  to  the  amount  and  kind  of  treatment  that  he  is 
about  to  prescribe;  and  it  will  urge  him  to  place  more  value  upon  an  examination 
of  the  patient,  and  of  the  cerebro-spinal  fluid  after  the  patient  has  received  treatment, 
than  he  has  been  accustomed  to  do  heretofore. 

Four  points  have  now  to  be  considered.  Two  of  these  occur  before  treatment  is 
begun,  and  two  after  it  has  stopped.  (1  and  2)  The  clinical  e\'idence  in  support 
of  the  early  infection  of  syphilis,  before  and  after  treatment.  (3  and  4)  The  patho- 
logical evidence  in  support  of  the  early  infection  of  syphilis,  before  and  after 
treatment. 

The  clinical  evidence  before  treatment  is  commenced  is  usually  slight  but 
unmistakable,  and  the  symptoms  are  usually  of  this  nature. 

Inequality  of  pupils,  irregularity  of  the  pupil  reflexes,  disturbances  in  the 
cranial  nerves,  altered  elbow  and  radial  reflexes,  altered  abdominal  and  cremaster 
reflexes,  increase  of  the  knee-jerks  on  one  or  both  sides,  occasionally  a  loss  of  reflexes, 
but  at  least  a  difference  in  the  reflexes  on  the  two  sides,  and  faint  alterations  in 
cutaneous  sensations. 

The  clinical  evidence  after  treatment  is,  as  a  rule,  more  pronounced,  and 
naturally  it  largely  depends  upon  the  nature  of  that  treatment. 

The  following  few  cases  will  give  some  idea  of  the  varied  manifestations  to  be 
met  with. 

Before  Treatment. 

Case  26. — A  man,  aged  27,  consulted  me  for  a  rash  which  was  a  papular 
syphilide.     The  primary  sore  had  just  healed.     The  pupils  were  unequal  and  acted 


THE    BIOLOGY    OF   SYPHILIS    OF   THE    NERVOUS    SYSTEM.  203 

feebly  to  light,  but  well  to  accommodation.  All  the  other  reflexes,  with  the  excep- 
tion of  the  cremaster  reflex  on  the  right  side,  could  not  be  obtained.  An  examina- 
tion of  the  cerebro-spinal  fluid  revealed  a  positive  lymphocytosis,  an  excess  of 
albumin  and  globulin,  and  a  positive  Wassermann  reaction. 

I  have  had  two  cases  in  which  the  patient  had  developed  typical  symptoms 
of  degenerative  meningo-m}-elitis  (tabes),  within  a  year  and  a  half  of  contracting 
the  disease. 

Case  27. — A  man,  aged  2.3,  with  veiy  severe  generalised  syphilis  of  six  months 
standing,  had  marked  symptoms  of  an  acute  meningo-encephalitis.  The  pupils 
were  unequal,  all  the  reflexes  in  the  body  were  much  exaggerated,  the  skin  was 
hyperaesthetic,  and  the  patient  complained  of  violent  headaches  and  sleeplessness. 

Examination  of  C.S.F.  :  Pressure  raised,  marked  lymphocytosis,  excess  of 
albumin  and  globulin,  Wassermann  reaction  positive. 

It  not  infrequently  happens  that  the  cases  with  the  severest  cutaneous 
manifestations  develop  meningo-encephalitis  and  meningo-myelitis. 

Case  28. — A  man,  aged  31,  had  a  chancre  nine  months  previously.,  'and  had  had 
the  usual  symptoms  of  generalised  syphilis,  for  which  he  had  received  no  treatment. 
He  then  came  up  for  advice,  complaining  of  very  bad  headaches.  As  the  patient 
appeared  rather  strange  he  was  admitted.  The  next  day  the  i^atient  had  a  fit,  and 
was  unconscious  for  two  days.  A  lumbar  puncture  was  done,  relie%'ing  the  condition 
only  slightly.  When  the  patient  regained  consciousness,  he  became  very  strange 
in  his  habits,  talked  gibberish  incessantly,  and  became  very  restless  and  excitable. 
A  week  later,  after  the  excitable  condition  had  given  waj-  to  a  more  morose  state, 
the  patient  became  unconscious  again,  and  died.  Post-mortem,  it  was  found  that 
the  patient  had  an  acute  meningo-encephalitis  and  myelitis.  There  were  some 
punctate  haemorrhages  in  the  cortex  of  the  brain,  and  these  were  especially  marked 
in  the  pons. 

Microscopically,  the  cortical  vessels  and  those  of  the  meninges  were  dilated 
and  surrounded  by  a  lymphocytic  infiltration. 

I  have  seen  another  case  similar  to  this,  and  the  condition  is  exactly  analogous 
to  the  haemorrhagic  encephalitis  which  follows  salvarsan — indeed,  it  is  the  same 
condition,  only  not  quite  so  acute. 

After  Treatment. 

Case  29. — A  man,  aged  26,  came  up  for  advice  concerning  further  treatment, 
having  contracted  syphilis  one  3-ear  previously,  for  which  he  had  been  treated  with 
salvarsan  and  mercury.  Patient  had  no  symptoms  of  a  nervous  affection  before 
treatment  began,  and  the  cerebro-spinal  fluid  was  normal. 


204  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF    SYPHILIS. 

The  only  sj-mptonis  of  which  the  patient  complained,  were  dull  sensations  in 
the  head,  which  came  on  every  third  or  fourth  day,  and  lasted  for  a  whole  day. 
Occasionally  the  patient  had  acute  pain  in  his  left  shoulder. 

The  pupils  were  unequal  and  acted  feebly  to  light,  and  there  was  slight 
nystagmus.  The  elbow  reflexes  could  not  be  obtained,  and  the  wrist  reflexes  were 
feeble.  The  abdominal  reflexes  were  difficult  to  obtain,  and  so  were  the  cremaster 
reflexes.  The  knee-jerks  were  quite  absent,  and  all  tendon  sensations  had  vanished. 
Rhomberg's  sign  was  present. 

The  cerebro-spinal  fluid  on  examination  gave  the  following  tests  :  Positive 
lymphocytosis  ;  Nonne-Apelt  reaction,  very  faintly  positive  :  heavy  precipi- 
tate with  salicyl-sulphonic  acid,  showing  excess  of  protein,  which  was  mainly 
albumin. 

Case  30. — A  patient  who  had  had  syphilis  for  nine  months  came  up  for  advice 
because  he  felt  run  down  and  could  not  sleep  well.  He  had  previously  been  treated 
with  salvar.san  and  mercury,  and  he  had  no  signs  or  syaiptoms  of  a  nervous  affection 
before  treatment  was  begun. 

Pupils  were  dilated  and  did  not  react  to  light,  all  the  reflexes  were  very  brisk, 
but  uneven,  the  abdominal  reflexes  on  one  side  being  more  pronoimced  than  on 
the  opposite  side.  No  ankle  clonus,  but  there  was  a  bilateral  Babinski's  phenomenon. 
Tactile  sensation  increased.  There  was  a  positive  lymphocytosis  of  the  cerebro- 
spinal fluid,  an  excess  of  albumin  and  globulin,  and  a  positive  Wassermann 
reaction. 

Case  31. — A  patient,  a  boy  aged  17,  contracted  syphilis  in  October,  and  came 
under  care  the  following  January,  being  covered  from  head  to  foot  with  a  diffuse 
papulo-erythematous  eruption.  After  eight  weekly  intravenous  injections  of  neo- 
salvarsan,  the  Wassermann  reaction  became  negative,  then  mercurial  injections 
were  carried  on  until  April.  Three  weeks  after  treatment  was  stopped,  the  patient 
began  to  complain  of  headache,  insomnia,  and  loss  of  appetite.  These  symptoms 
became  graduall}'  worse,  and  he  came  up  for  advice  again  in  June,  by  which  time 
he  had  lost  2|  stones  in  weight.  ■  The  boy  looked  pale  and  emaciated,  the  pupils 
were  slightly  unequal,  and  the  reflexes  were  on  the  plus  side,  and  there  was  a  general 
hyperaesthesia,  otherwise  nothing  abnormal  was  discovered — Wassermann 
reaction  was  negative.  Fearing  cerebro-spinal  syphilis,  a  lumbar  puncture  was 
performed,  with  the  following  extraordinary  result : — 

Cells:  450  per  cubic ,  millimetre  ;  68  per  cent,  lymphocytes;  27  per  cent. 
endothelial  cells  ;  5  per  cent,  polymorphonuclears. 

Nonne-Apelt  reaction  positive. 

Wassermann   reaction   positive   in  all  dilutions,  i.e.,  from  10  to  500  per  cent. 


THE    BIOLOGY   OF   SYPHILIS   OF   THE    NERVOUS   SYSTEM.  205 

The  patient  had  no  symptoms  of  a  nervous  infection  before  treatment  was  com- 
menced, but  unfortunately  his  cerebro-spinal  fluid  was  not  tested. 

The  pathological  evidence  of  an  earlj^  infection  of  the  nervous  system  has  to  be 
most  carefully  considered,  as  the  difference  between  a  normal  and  a  jDathological 
cerebro-spinal  fluid  is  a  matter  of  personal  observation,  and  hence  varies  somewhat. 

If  there  is  a  positive  lymphocytosis,  a  positive  phase  I,  and  a  positive  Wasser- 
mann  reaction,  the  evidence  is  complete  ;  but  a  cerebro-spinal  fluid  may  be  patho- 
logical, long  before  the  tests  just  mentioned  are  given.  The  very  first  change  from 
a  normal  to  a  pathological  cerebro-spinal  fluid  is,  in  my  experience,  an  increase  of 
the  albumin,  and  then  the  number  of  lymphocytes,  begins  to  increase,  and  there 
may  be  a  well  marked  lymphocytosis  before  there  is  an  ascertainable  increase  in 
the  amount  of  globulin. 

An  excess  of  albumin  in  the  cerebro-spinal  fluid,  before  treatment  is  com- 
menced, I  regard  as  pathological.  There  are  two  good  methods  of  testing  quanti- 
tatively for  albumin.  The  globulin  can  be  precipitated  by  ammonium  sulphate  and 
separated  off,  and  then  the  filtrate  is  subjected  to  Heller's  test  in  varying  dilutions  ; 
or  the  observer  can,  by  examining  several  normal  cases,  get  a  mental  picture  of  the 
usual  density  of  the  solution,  to  which  a  few  drops  of  a  saturated  solution  of  salicyl- 
sulphonic  acid  have  been  added,  and  any  increase  of  this  density,  or  the  formation 
of  a  definite  precipitate  at  once  will  mean  that  there  is  an  excess  of  protein. 

After  treatment,  one  has  to  be  more  cautious,  as  salvarsan  increases  the  amount 
of  both  albunain  and  globulin  in  the  cerebro-spinal  fluid  of  cases  which  have  never 
been  infected  with  syphilis. 

I  am,  as  yet,  unable  to  say  for  certain  jvhat  is  the  best  time  to  examine  the 
cerebro-spinal  fluid  after  salvarsan,  and  w-hat  is  the  limit  of  the  period  when 
the  salvarsan  action  can  be  disregarded.  In  my  opinion,  if  any  intraspinal 
injections  of  salvarsanised  serum  are  to  be  given,  after  the  ordinary  intravenous 
injections  have  been  suspended,  they  should  be  given  as  quickly  as  possible  after- 
wards. I  make  the  rule  myself  to  examine  the  cerebro-spinal  fluid  one  week  after 
the  last  intravenous  injection,  and  if  I  think  the  cerebro-spinal  fluid  contains  more 
protein  than  could  possibly  be  accounted  for  by  the  salvarsan,  I  regard  the  fluid 
as  pathological.  One's  opinion  may  be  fm'ther  backed  up  by  a  careful  count  of  the 
lymphocytes,  and  by  the  result  of  the  goldsol  reaction. 

At  this  stage  it  is  not  worth  while  doing  the  Wassermann  reaction,  and  no 
reliance  at  all  must  be  placed  upon  the  pressure  of  the  fluid,  since  salvarsan  may 
considerably  raise  the  pressure,  or  it  may  not  alter  it. 

A  few  cases  will  now  be  given  illustrating  these  points. 

Case  32. — Syphilis  contracted  January,  1913.     Examination  of  C.S.F.  in  June, 


206  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

1914,  was  normal.  As  patient  had  a  recurrent  syphilitic  rash,  he  was  given  seven 
intravenous  injections  of  "  914."  Examination  of  C.S.F.  seventeen  hours  after 
last  injection.  Pressiue  very  much  raised.  Lymphocytosis  16  per  cubic  millimetre. 
Faint  ring  with  amnioiiium  sulphate  and  faint  opacity  on  shaking.  Dense 
opacity  with  salicyl-sulphonic  acid,  and  an  instantaneous  floccident  precipitate 
with  acetic  acid  and  potassium  ferrocyanide.  Goldsol  reaction  not  tried.  I 
considered  that  this  patient's  central  nervous  system  was  affected. 

Case  3.3. — Early  generalised  syphilis.  C.S.F.  normal  before  treatment.  Examined 
twenty-four  hours  after  the  seventh  intravenous  injections  of  "  914."  Pressure  not 
raised.  No  lymphocytosis.  No  ring  or  opacity  with,  ammonium  sulphate. 
Fairly  dense  opacity  with  salicyl-sulphonic  acid  (undoubted  excess  of  albumin). 
Goldsol  reaction  negative.  In  my  opinion  patient  merely  had  an  increase  of 
albumin,  due  to  the  salvarsan. 

Case  34. — Early  generalised  syphilis.  C.S.F.  normal  before  treatment.  Two 
weeks  after  eighth  intravenous  injection  of  "  914."  Pressure  slightly  raised.  No 
lymphocytosis.  No  ring  or  opacity  with  ammonium  sulphate.  Faint  opacity  with 
salicyl-sulphonic  acid.  Goldsol  reaction  negative.  This  C.S.F.  could  be  regarded 
as  normal. 

Case  35. — Syphilis  contracted  1911.  L.  hemiplegia  Januarj-,  1914.  Examined 
October,  1914.  All  reflexes  plus,  pupils  unequal  R.  >  L.,  and  reflexes  of  R.  <  L. 
C.S.F.  before  treatment.  Pressure  not  raised.  Lymphocytes  14  per  c.mm.  Ring 
and  opacity  with  ammonium  sulphate.  Dense  opacity  with  salicyl-sulphonic  acid. 
Marked  turbidity  with  acetic  acid  and  potassium  ferrocyanide.  Goldsol  reaction 
positive.  C.S.F.  tested  ten  days  after  second  intravenous  injection  of  neo-salvarsan. 
Pressure  enormously  raised.  Lymphocytosis  130  per  c.mm.  Fainter  ring  and 
opacity  with  ammonium  sulphate.  Dense  precipitate  with  salicyl-sulphonic  acid. 
Goldsol  reaction  negative.  Salvarsan  had  temporarily  destroyed  the  specific 
lipoid-globulin,  and  the  formation  of  the  new  lipoid-globulin  was  being  preceded  by 
a  tremendous  increase  of  the  albumin. 

Case  36. — Treatment  begun  before  patient  reached  generalised  stage.  C.S.F. 
examined  one  week  after  the  seventh  intravenous  injection  of  "  914."  Pressure 
not  raised.  No  lymphocytosis.  No  ring  or  opacity  with  ammonium  sulphate. 
Fairly  dense  opacity  with  salicyl-sulphonic  acid.  Goldsol  reaction  negative.  In 
this  case,  slight  increase  of  albumin  due  to  the  salvarsan. 

Summary. — That  syphilitic  invasion  of  the  central  nervous  S3'stem  occurs 
during  the  generalisation  stage,  and  any  lesions  which  appear  later,  date  from  this 
invasion.  The  administration  of  treatment  will  often  provoke  pathological  changes 
in  the  cerebro-spinal  fluid,  but,  before  the  changes  are  considered  to  be  pathological. 


•      THE    BIOLOGY   OF   SYPHILIS    OF   THE    NERVOUS    SYSTEM.  207 

it  must  be  remembered  that  salvarsan  has  the  action  of  raising  the  ]iressure, 
increasing  the  albumin  and  the  globulin,  and  slightly  raising  the  cell  count  in  a 
normal  individual.  The  duration  of  this  action  of  salvarsan  has  yet  to  be 
determined. 


(b)   The  Paths  and  Sites  of  Infection  of  the  Syphilitic  Lesions  of  the 

Central  Nervous  System. 

The  apparently  slow  onset  of  nervous  lesions  appears  to  have  induced  the 
belief  that  the  infection  would  probably  originate  by  passage  along  the  nerves  or 
their  lymphatics,  and  not  b}'  way  of  the  blood  stream. 

A  good  deal  of  experimental  work  has  been  carried  out,  with  a  view  to  determine 
which  of  these  paths  is  taken  by  the  organism,  in  its  journey  to  the  nervous  system. 
While  realising  that  the  nervous  path  is  a  possible  channel  of  infection,  I  believe 
that  enough  attention  has  not  been  devoted  to  the  possibility  of  infection  by  means 
of  the  general  systemic  circulation,  and  I  propose  to  advance  reasons  for  this 
opinion.  I  have  gradually  reached  the  view,  namely,  that  the  infection  of  the  central 
nervous  system  is  usually,  if  not  always,  haematogenous  in  origin. 

Before,  however,  putting  forward  my  own  point  of  view,  the  experimental 
work  dealing  with  infection  by  a  neurogenic  channel  will  be  considered. 

The  route  of  infection  of  the  central  nervous  system  has  been  worked  at 
experimentally  by  Weygandt  and  Jakob. ^ 

These  observers  injected  syphilitic  material  into  rabbits,  using  both  the 
testicular  and  intravenous  routes.  They  found  that  50  per  cent,  of  the  animals 
showed  changes  in  the  central  nervous  system,  and  that  these  changes  were  the 
same,  whichever  route  was  adopted. 

The  lesions  fomid  can  be  classified  under  three  main  headings,  in  order  of 
frequency,  viz.  :  (1)  leptomeningitis  of  the  brain  and  cord ;  (2)  inflammatory 
changes  in  the  perineural  sheaths  of  nerve  roots  as  they  left  the  cord ;  and  (3) 
inflammatory  changes  in  the  connective  tissue  coverings  of  the  peripheral  nerves. 

In  all  these  lesions,  the  blood-vessels  showed  inflammatory  changes,  and  were 
surrounded  with  lymphocytes  and  plasma  cells.  Some  blood-vessels  in  this  con- 
dition were  also  to  be  seen,  in  the  brain  and  cord. 

In  a  few  cases,  the  vessels  in  the  brain  cortex  showed  marked  inflammatory 
changes  ;  and  scattered  areas  of  cellular  infiltration  occurred  in  the  nerve  substance, 
and  a  marked  proliferation  of  glial  cells,  without  any  changes  in  the  pia-arachnoid. 

In  a  minority  of  these  cases,  the  areas  of  cellular  infiltration  in  the  nerve 
substance  showed  considerable  resemblance  to  gummata. 

o 


208  THE    BIOLOGY,    CLINICAL   ASPECT    AND    TREATMENT   OF    SYPHILIS. 

The  two  points  in  Weygandt  and  Jakob's  work  that  are  most  striking  are:  (1) 
that  although  inflammatory  changes  were  to  be  found  in  the  perineural  sheaths 
of  nerves,  it  was  around  the  blood-vessels  in  the  connective  tissue  that  they  were 
most  marked  ;  and  (2)  that  the  lesions  of  the  central  nervous  system  were  the 
same,  whether  they  were  from  a  testicular  or  an  intravenous  infection. 

In  England,  owing  to  the  work  of  Orr  and  Rows,-  many  neurologists  believe 
that  an  important  path,  along  which  infection  is  carried  to  the  nervous  system,  is 
the  lymphatic  system  of  the  peripheral  nerves.  It  should  be  stated  first,  that  Orr 
and  Rows  did  not  work  vnth.  syphilis,  and  only  presumed  what  might  occm-  in  this 
disease,  from  the  knowledge  they  had  gained  in  watching  the  paths  along  which 
toxines  spread,  from  injected  staphylococcic  material  in  rabbits. 

Orr  and  Rows  concluded  from  these  observations  : — 

(1)  That  the  lesion  in  the  spinal  cord  always  corresponded  with  the  nerve  supply 
of  the  infective  focus. 

(2)  That  the  degeneration  of  the  intramedullarj-  portion  of  the  spinal  roots 
commenced  at  the  point  where  the  neurilemma  sheath  was  lost. 

(3)  That  the  posterior  root  entry  zone  was  always  most  affected. 

(4)  That,  as  examination  of  the  extramedullary  portion  of  the  nerves  yielded 
a  negative  result,  it  seemed  correct  to  assume  that  toxines  could,  in  certain  cases, 
ascend  along  the  perineural  lymphatics,  ^vithout  producing  parenchymatous  changes 
in  the  nerves. 

In  their  experimental  work,  they  placed  a  celloidin  capsule  containing  a  broth 
culture  of  Staphylococcus  albus  in  contact  with  the  nerve,  and  found  that  inflam- 
matory phenomena  could  be  traced  upwards  to  the  posterior  root  ganglion,  and 
beyond  it,  into  the  spinal  roots. 

Orr  and  Rows  infection  by  the  haematogenous  route  also  produced  change;, 
which  allowed  them  to  separate,  by  histological  means,  a  haematogenous  from  a 
lymphogenous  lesion.     In  lymphogenous  infection  they  found  : — 

(1)  Inflammatory  reaction  of  the  cells  of  the  fixed  connective  tissue. 

(2)  Proliferation  of  the  cells  of  the  adventitial  sheath  of  the  veins  aM  capil- 
laries. 

(3)  The  appearance  of  scavenger  cells  where  the  myelin  was  disintegrated. 

(4)  Nerve  cell  degeneration  and  neuronophagic  phenomena. 
In  haematogenous  infection  they  found  : — 

(1)  The  most  highly  developed  structure — the  nerve  cell — suffering  least  of  all. 

(2)  A  primary  degeneration  of  the  myelin  sheath  around   the  margin  of  the 

cord,  and  on  either  side  of  the  postero-median  septum. 

(3)  That  the  in3-elin  degeneration  was  greatest  in  the  upper  part  of  the  cord. 


THE    BIOLOGY   OF   SYPHILIS    OF   THE    NERVOUS    SYSTEM.  209 

(4)  Marked  oedema  of  the  cord. 

(5)  The  vessel  walls  showing  hyalin  degeneration,  and  containing  thrombi  of 

the  same  nature. 

From  these  observations,  Orr  and  Rows  offer  the  opinion  that  tabes  dorsalis 
and  general  paralysis  of  the  insane  are  lymphogenous  infections,  and  they  state 
that  the  distribution  of  the  former,  and  the  histological  characters  of  both,  are 
similar  to  those  produced  by  infection  of  the  lymph  stream  of  nerves. 

The  points  raised  by  these  investigations  may  now  be  considered  in  somewhat 
greater  detail. 

Orr  and  Rows  state  : — 

(1)  That  the  lesion  in  the  spinal  cord  always  corresponded  with  the  nerve  supply 
of  the  infective  focus.  It  may,  however,  be  pointed  out,  that  we  do  not  find  that 
digital  or  cephalic  chancres  are  more  prone  to  be  followed  by  degenerative 
encephalitis  or  degenerative  myelitis  of  the  cer\4cal  region  than  are  genital 
chancres. 

(2)  They  found  that  the  degeneration  of  the  intramedullary  portion  of  the 
spinal  roots  commenced  at  the  point  where  the  neurilemma  sheath  was  lost.  This 
part  is,  however,  frequently  not  affected  in  degenerative  myelitis,  but  it  would 
be  affected,  were  the  mode  of  infection  an  ascending  one,  by  means  of  a  nerve  root. 

(3)  That  the  posterior  root  entry  zone  was  always  most  affected.  In  degenera- 
tive myelitis,  however,  this  part  may  not  be  affected  at  all. 

(4)  That  as  examination  of  the  extramedullary  portion  of  the  nerves  yielded 
a  negative  result,  it  seemed  correct  to  assume  that  toxines  could,  in  certain  cases, 
ascend  along  the  perineural  lymphatics  without  producing  parenchymatous  changes 
in  the  nerves. 

In  syphilis  of  the  nervous  system,  we  are  dealing  with  live  organisms,  not  with 
their  toxines.  Although  highly  improbable  that  a  leptomeningitis  ma)'  result  in 
this  way,  it  is  theoretically  possible. 

It  appears  to  me,  that  Orr  and  Rows  observations  are  hardly  in  accordance  with 
established  clinical  facts,  and  that  it  would  be  an  error  to  lay  too  much  stress  upon 
them.  Further,  I  have  been  unable  to  distinguish  any  differences  which  could  be 
attributed  to  variation  of  route,  in  a  large  number  of  cases  of  degenerative  ence- 
phalitis which  I  have  examined  histological!}',  and  I  am  not  inclined  to  believe 
that  the  routes,  whether  haematogenous  or  lymphogenous,  can  be  differentiated. 

On  the  other  hand,  it  is  possible  to  distinguish  whether  the  infection  occurred 
primarih'  in  the  meninges,  or  in  the  brain  substance. 

If  the  brain  from  a  case  of  degenerative  encephalitis  be  examined,  pro- 
vided the  meninges  still  show  signs  of  inflammation,  vessels  will  be  seen   running 

02 


210  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   SYPHILIS. 

into  the  brain  substance  from  the  pia  mater,  and  it  is  mostly  in  the  wails  of  these 
vessels  that  the  phases  of  the  leucocytozoon  are  to  be  found  (Plate  12  (1) ).  The  main 
exception  to  the  above  rule  is,  that  the  Spirochaeta  pallida  does  not  necessarily 
follow  the  route  taken  by  the  vessels  ;  it  may  wander  and  be  found  anywhere. 

In  most  cases  of  degenerative  encephalitis,  acute  or  chronic  inflammatory 
changes  are  to  be  found  in  the  pia-arachnoid.  In  early  cases,  the  inflammation  in 
the  leptomeninx  may  be  acute,  and  acute  inflammatory  changes  are  to  be  found 
in  the  superficial  part  of  the  grey  matter.  In  both  situations,  one  finds  the  phases 
of  the  leucocytozoon  (Plate  33  (1) ),  but  in  only  the  latter  are  the  spirochaetae  to  be 
found.  In  late  cases,  the  acute  inflammation  has  reached  the  white  matter,  in 
which  the  phases  of  the  leucocytozoon  can  also  be  demonstrated.  In  some  cases 
of  degenerative  encephalitis,  on  the  other  hand,  no  meningeal  changes  are  to  be 
found.     In  these  cases  the  process  begins  in  the  brain  substance  itself. 

Probably,  in  the  majority  of  the  cases  of  syphilis,  the  organisms  get  into  the 
meninges  by  means  of  the  blood-vessels.  They  may  give  rise  to  no  symptoms ; 
their  spread  may  not  even  be  noticed,  but,  when  they  later  give  rise  to  symptoms, 
degenerative  myelitis  or  encephalitis  is  the  result. 

My  reasons  for  thinking  that  these  two  degenerative  affections  arise  in  probably 
the  greater  majority  of  the  cases,  the  smaller  minority  being  ameningeal  in  origin, 
by  a  direct  extension  of  the  organisms  from  the  meninges,  are  the  following  : — 

The  meninges  of  the  brain  are  most  closely  attached  to  the  brain  substance 
over  the  cortex,  and,  in  cases  of  degenerative  encephalitis,  the  blood-vessels  run 
directly  from  the  meninges  into  the  nerve  tissue.  In  all  cases  of  degenerative 
encephalitis,  the  morbid  changes  are  limited  practically  to  the  cortex,  and,  the 
earlier  the  case,  the  nearer  to  the  surface  are  the  histological  changes  to  be  found ; 
while  in  late  cases,  only  the  superficial  jjart  of  the  cortex  may  show  the  results  of 
inflammation,  the  recent  areas  being  deeply  situated. 

In  the  case  of  the  cord,  the  blood-vessels  run  from  the  meninges  along  the 
septum  posticum,  into  the  posterior  columns.  Hence  the  ease  Mith  which  the 
organisms  in  the  meninges  can  invade  the  cord  and  produce  degenerative  "myelitis, 
which,  in  nearly  all  cases,  is  a  lesion  of  the  posterior  part  of  the  cord. 

Early  syphilitic  lesions  of  the  cord  usually  affect  the  anterior  part,  and  the 
myelitis  which  results  is,  in  my  opinion,  an  endarteritic  lesion,  analogous  to  that 
endarteritic  lesion  of  the  brain  which  causes  hemiplegia,  itself  a  frequent  early 
symptom  of  syphilis. 

The  anterior  surface  of  the  cord  corresponds  to  the  base  of  the  brain  :  the 
blood  supply  to  both  comes  from  the  same  source.  There  is  no  anterior  meningeal 
ligament   along   which    organisms   can   spread ;    the   main   blood-vessel    is    free. 


Plate  33. 


A  section  through  the  pia- arachnoid  covtring  the  cerebral  cortex  from  a 
case  of  degenerative  encephalitis.  The  pha.se  of  the  leucocytozoon  depicted, 
is  a  female  gametocyte,  containing  one  blepharopla.st. 


Schematic  repre&ehtation    of   the  various   phases'  of    the   Leucocytozoon 
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Plate  33. 


THE    BIOLOGY   OF   SYPHILIS    OF   THE   NERVOUS    SYSTEM.  211 

Therefore,  one  might  imagine  a  lesion  of  the  anterior  part  of  the  cord  to  be  of  the 
nature  of  an  endarteritis. 

The  early  endarteritic  lesions  of  syphilis  are  peculiarly  localised,  and  they  are 
due  to  the  direct  local  action  of  the  organism,  which  starts  its  life-cycle  in  the  coats 
of  the  vessel,  a  point  I  have  been  able  to  follow.  As  the  cycle  may  start  in  one 
part,  and  not  necessarily  in  the  whole  circumference  of  the  vessel,  the  unipolar 
changes  to  be  met  with  are  accounted  for.  In  time,  the  organism  may  spread 
beyond  the  vessel  into  the  nerve  substance,  and,  if  it  did  so  in  the  anterior  part 
of  the  cord,  it  would  immediately  cause  nerve  degeneration.  This  is  probably  the 
pathology  of  those  late  anterior  horn  lesions  which  are  occasionally  to  be  met  with 
in  syphilis. 

Lateral  column  lesions  are  also  be  to  met  with,  although  very  rarely,  in  spite 
of  the  close  connection  this  part  of  the  cord  has  with  the  meninges,  through  the 
ligamerita  denticulata.  The  reason  is  that  there  is  no  direct  blood  supply  between 
the  two  at  this  point. 

Direct  extension  of  the  organisms  into  the  central  nervous  system,  by  way  of 
the  peripheral  nerve  trunks,  most  probably  never  occurs,  for  the  simple  reason  that 
lesions  of  nerves,  along  which  the  organisms  have  spread,  give  rise  to  symptoms  early 
in  the  disease.  Moreover,  peripheral  syphilitic  nerve  lesions  affect  both  motor 
and  sensory  nerves.  Again,  a  posterior  column  lesion  frequently  exists,  without 
a  corresponding  lesion  in  the  posterior  root  ganglion,  and  I  am  unaware  that 
syphilitic  root  neuritis  is  followed  by  degenerative  myelitis  (tabes). 

Finally,  early  cranial  nerve  lesions,  which  arise  at  the  time  when  almost  every 
nook  and  crevice  in  the  body  is  being  infested  with  organisms,  are  undoubtedly 
secondary  to  inflammation  of  the  meninges  surrounding  them.  The  nerves  most 
commonly  affected  are  the  second,  eighth  and  seventh,  all  nerves  which  have  to 
go  through  small  bony  foramina.  Therefore,  any  increase  in  the  bulk  of  the  meninges 
would  make  the  foramina  smaller  still,  and  the  nerves  would  degenerate  by  the 
increased  pressure  produced  thereby. 

To  prove  that  these  early  cranial  nerve  lesions  are  primarily  meningeal  in 
origin,  one  only  has  to  examine  the  cerebro-spinal  fluid,  when  often  as  many  as 
600  cells  per  c.mm.  are  to  be  found.  Furthermore,  the  administration  of  adequate 
treatment,  provided  it  is  prescribed  early  enough,  completely  and  quickly  cures 
the  lesion,  which  would  certainly  not  be  the  case  if  the  infection  were  primarily 
in  the  nerve. 

One  of  the  chief  reasons  observers  give  to  explain  the  occurrence  of  degenerative 
myelitis,  from  a  spread  of  the  organisms  along  the  posterior  root  sheaths,  is  that  the 
Spirochaeta  pallida  has  been  found  in  sections  of  a  chancre  in  the  nerves  of  the  skin. 


212  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT    OF   SYPHILIS. 

In  my  opinion,  such  an  occurrence  is  a  coincidence,  since  the  Spirochaeta  pallida, 
owing  to  its  motility,  can  be  found  in  any  tissue.  Since  the  Spirochaeta  pallida  is 
not  the  direct  cause  of  syphilis,  its  extension  along  the  lymphatic  sheaths  of  the 
posterior  root  nerves  would  not  give  rise  to  degenerative  myelitis.  For  symptoms 
of  syphilis  to  occur,  the  whole  of  the  life-cycle  of  the  j^rotozoon  nnist  take  place  in 
loco,  therefore  the  spores  and  the  other  phases  must  be  present  in  the  brain  and 
spinal  cord  in  cases  of  degenerative  encephalitis  and  myelitis.  I  have  examined 
brains  from  ten  cases  of  degenerative  encephalitis,  and  in  nine  of  them  I  have 
found  the  phases  of  the  leucocytozoon,  which  mostly  occurred  in  the  walls  of  the 
blood-vessels,  while  the  Spirochaeta  pallida  had  no  particular  distribution. 

There  are  two  points  to  which  I  would  like  to  refer,  before  discussing  the 
subject  in  hand  from  other  points  of  \'iew.  One  is  that  many  cases  of 
degenerative  encephalitis  die,  not  from  a  fresh  outbreak  of  symptoms,  or  from  a 
fresh  development  of  the  spirochaetae,  but  from  a  haemorrhagic  encephalitis  caused 
by  the  pneumotoxine,  and  possibly  by  other  toxines  as  well. 

The  other  point  is,  that  syphilitic  affections  of  nerve  tissue  may  be  dependent 
upon  primary  venous  lesions.  The  role  played  by  phlebitis  in  the  causation  of 
lesions  other  than  those  that  can  be  observed  under  the  skin,  is,  one  might  say, 
quite  unknown. 

A  great  deal  of  work  is  required  in  this  direction,  as  veins  are  commonly 
afEected  in  syphilis,  and  syphilitic  phlebitis  exhibits  phenomena  which  I  have  not 
observed  in  any  other  disease. 

A  most  interesting  point  which  now  crops  up  is,  why  should  degenerative 
encephahtis  and  myelitis — two  parenchymatous  lesions — be,  broadly  speaking, 
incurable,  while  meningeal  syphilis  is  curable  ?  To  my  mind,  the  whole  difference 
depends  upon  the  number  of  organisms  which  develop  extramurally,  i.e.,  away 
from  the  walls  of  blood-vessels,  and  over  how  much  nerve  matter  tlieir  development 
spreads. 

In  the  severest  cases  of  degenerative  encephalitis  all  the  phases  of  the  leuco- 
cytozoon can  be  found  scattered  about  in  the  nerve  substance  away  from  the  blood- 
vessels, while  in  the  early  cases,  and  probabl_y  in  meningeal  syphilis,  and  in 
meningo-encephalitis  and  myelitis  they  are  only  found  in  the  walls  of  the  blood- 
vessels. Moreover,  the  development  of  the  spirochaetae  is  very  much  more  pro- 
nounced in  the  degenerative  lesions,  especially  is  this  the  case  in  degenerative 
encephalitis.  They  develop  more  or  less  independently  of  the  other  phases  ;  they 
wander  away  from  blood  vessels  and  Ij^mphatics,  flourish  at  the  expense  of  the 
nerve  cells,  and  cannot  be  reached  by  drugs,  however  given. 

There  is  sufficient  clinical   evidence  alone,  in  favour  of  an  haematogeneous 


THE    BIOLOGY   OF    SYPHILIS    OF   THE    NERVOUS    SYSTEM.  213 

origin  of  syphilitic  nervous  lesions,  without  having  recourse  to  experimental 
work.  Hemiplegia  and  transverse  myelitis  are  true  vascular  lesions,  so  are  those 
cases  of  hacmorrhagic  encephalitis  occurring  either  before  or  after  salvarsan.  If 
we  ask  ourselves  what  becomes  of  these  early  nervous  lesions,  we  shall  see  that 
new  light  will  be  thrown  upon  the  pathology  of  the  late  degenerative  encephalitis 
and  myelitis. 

It  must  be  remembered  that  there  are  many  cases  which  are  on  the  verge  of 
developing  any  one  of  the  above-mentioned  vascular  lesions,  and  that  the  develop- 
ment is  prevented  by  timely  treatment.  There  must  also  be  many  cases  in  which 
the  spores  are  present  in  the  vessels,  and  in  those  positions  in  which,  should  they 
develop,  any  one  of  the  above  lesions  would  be  produced  ;  but  these  cases  develop 
only  in  later  years,  when  the  symptoms  are  somewhat  different. 

Let  us  take,  first  of  all,  that  group  of  cases  in  which  there  have  been  early 
vascular  nervous  lesions,  and  see  what  becomes  of  them.  Most  recover  from  the 
symptoms,  provided  the  treatment  is  sufficient,  early  prescribed,  and  sufficiently 
drastic.  If,  on  the  other  hand,  the  treatment  is  not  prescribed  early  enough  after 
the  onset  of  the  symptoms,  and  is  not  sufficiently  powerful  to  kill  all  the  organisms, 
there  is  a  tendency  for  the  organisms  to  spread  peripherally,  just  as  they  do  in  the 
skin  ;  and,  should  they  develop  later,  it  will  be  in  nerve  tissue  proper,  and  it  will 
not  be  merely  limited  to  a  blood-vessel,  consequently  nerve  degeneration  will  follow. 

Amongst  my  notes  I  have  two  cases  of  degenerative  encephalitis,  in 
which  the  patients  some  years  previously  had  had  a  hemiplegia.  One  case  of 
degenerative  encephalitis  had  had  aphasia  and  other  symptoms  of  an  encephalitis, 
twelve  years  before  the  onset  of  the  degenerative  lesion.  Two  cases  of 
degenerative  myelitis  which  had  followed  a  transverse  myelitis,  and  three 
cases  of  degenerative  myelitis,  which  began  with  a  peroneal  palsy.  Macnamara* 
pubhshed  an  interesting  case  of  syphilis  with  Landry's  syndrome,  with  later 
development  of  degenerative  m3'elitis. 

Think  of  the  number  of  cases  there  must  be,  then,  of  degenerative  encephalitis 
and  myelitis  which  have  arisen  without  any  previous  symptoms  of  a  vascular  lesion. 
The  same  thing  happens  in  the  skin.  The  patient's  first  rash  may  be  a  recurrent 
syphilide  or  a  gumma. 

An  early  hemiplegia  usually  results  from  a  thrombosis  of  the  middle  cerebral 
artery,  or  one  of  its  branches,  in  the  sylvian  fissure.  If  the  organisms  radiate  from 
these  branches,  they  will  ultimately  reach  the  teraporo-sphenoidal  lobe.  It  is  not 
at  all  uncommon  to  find  in  cases  of  degenerative  encephalitis,  that  the  part  of  the 
brain  most  affected  is  the  temporo-sphenoidal  lobe,  another  point  in  favour  of  the 
haematogeneous  origin  of  the  syphilitic  nervous  lesions. 


214  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   SYPHILIS. 

There  is  another  important  point  in  favour  of  the  haematogeneous  route,  nnd 
it  should  be  brought  forward. 

The  Leucocytozoon  syphilidis  is  carried  all  over  the  body  by  the  blood  stream, 
and  the  spores,  as  they  develop  in  either  endothelial  cells  or  connective-tissue  cells, 
first  of  all  remain  in  the  blood-vessel,  in  which  they  develop.  The  more  pronounced 
their  development,  the  greater  will  be  the  area  over  which  the  bodies  that  ultimately 
arise  from  them  will  spread.  The  area  covered  by  the  spread  mil  also  naturally 
depend  upon  the  motility  of  the  phases,  i.e.,  the  more  motile  the  phase,  the  greater 
the  area  it  will  encroach  upon.  The  most  motile  part  of  the  Leucocytozoon  sypJiilidis 
is  the  male.  Now  the  male  phase  can  develop  extracellularly,  and  is  the  main  cause 
of  the  symptoms. 

The  extracellular  development  will  take  place  onlj'  provided  the  pabulum  on 
which  it  is  growing  is  suitable.  Nerve  tissue,  owing  to  its  richness  in  hpoid- 
globulins,  is  just  the  medium  for  the  extracellular  development  of  the  male  phase, 
consequently  spirochaetae  are  to  be  found  in  abundance  in  certain  positions  in 
degenerative  encephalitis,  and  naturally  they  will  have  no  special  locahsation. 
To  make  this  part  of  our  subject  a  little  clearer,  an  analogy  will  be  drawn  between 
what  happens  in  the  skin  and  in  the  nervous  system. 

In  early  generalised  syphilis,  the  cortex  of  the  brain  may  be  affected  by  lesions 
which  are  primarily  vascular  in  origin,  analogous  to  the  common  cutaneous  lesions. 

Later  in  the  disease,  one  knows  that  the  cutaneous  lesion,  instead  of  being  a 
small  lesion  like  a  papule,  is  a  large  lesion,  which  is  often  made  up  of  several 
papules,  as  a  serpiginous  syphilide,  for  instance.  The  recurrent  cutaneous  lesions 
are  in  circles,  or  in  cycloid  forms,  owing  to  the  peripheral  spread  of  the  organisms 
from  the  original  papule  which  preceded  the  recurrent  lesion. 

A  similar  state  of  affairs  can  also  occur  in  the  central  nervous  system.  If  they 
occur  in  the  cortex  of  the  brain,  and  if  the  organisms  do  not  develop  outside  of  the 
vessels,  and  if  the  spirochaetae  do  not  multiply  extracellularly,  the  lesion  will  be 
one  of  encephalitis,  and  non-degenerative.  Such  cases  usually  develop  symptoms 
about  the  fourth  year  after  infection,  and  are  usually  diagnosed  as  cerebral  syphihs. 
If  the  symptoms  occur  later,  we  are  often  in  a  position  of  being  unable  to  differentiate 
the  condition  from  initial  degenerative  encephahtis,  which  differs  from  ordinary 
encephalitis  only  in  that  the  organisms  develop  outside  the  vessels,  and  that  the 
spirochaetae  multiply  extracellularly.  On  two  occasions  I  have  treated,  by 
intrathecal  injections  of  salvarsanised  serum,  cases  which  have  been  diagnosed 
by  well-known  nem-ologists  and  by  myself  as  degenerative  encephahtis,  and  they 
recovered  completeh',  showing  that  our  original  diagnosis  was  incorrect. 

Should  a  condition  analogous  to  an  orbicular  or  serpiginous  syphihde  occur  in 


THE    BIOLOGY    OF    SYrHILIS   OF   THE   XER\  OUS   SYSTEM.  215 

the  cord,  if  about  the  fourth  year,  it  is  diagnosed  correctly  as  spinal  sypliiiis,  or 
better,  non-degenerative  myelitis  ;  if  it  occurs  later,  then  it  may  so  closely  simulate 
degenerative  myelitis  that  the  two  cannot  be  difEerentiated. 

I  remember  well  a  case  which  had  all  the  symptoms  of  degenerative  myelitis, 
viz.,  Ai-gyll-Robertson  pupils,  lightning  pains,  ataxia,  bladder  trouble,  and  loss 
of  erections,  symptoms  which  entirely  disappeared  after  two  intravenous  injections 
of  "  606."  The  injections  were  given  over  four  years  ago,  and  the  patient  so 
far  has  had  no  recm'rence. 

Naturally,  cases  which  are  neither  wholly  degenerative  nor  wholly  non- 
degenerative  are  to  be  met  with,  and,  as  already  mentioned,  non-degenerative  lesions 
may  ultimately  become  degenerative.  The  syphilitic  organism  may,  early  in  the 
disease,  affect  the  main  vessel  whose  branches  go  to  the  skin,  and  so  cause  endarteritis, 
which  may  result  in  an  aneurysm. 

I  once  had  a  case  of  popliteal  aneurysm  which  occurred  three  years  after  the 
infection,  and,  six  months  later,  a  popliteal  aneurysm  formed  on  the  opposite  side. 

The  main  trunk,  which  sends  branches  to  the  cortex,  may  frequently  be 
involved  very  early  in  the  disease,  and  may  give  rise  to  hemiplegia,  which  may 
also  be  bilateral,  as  in  the  above  case. 

In  later  years,  any  part  of  the  artery,  from  the  trunk  to  a  terminal  branch  in 
the  skin,  may  be  the  focus  where  the  leucocytozoon  starts  its  life-cycle  again.  Owing 
to  the  time  the  organism  has  been  in  the  host,  and  the  efforts  which  the  host  has 
made  to  overcome  it,  the  damage  wrought  by  the  organism  will  be  more  localised, 
but  on  a  relatively  greater  scale,  and  the  resistance  offered  by  the  host  will  bear  a 
ratio  thereto,  with  the  result  that  the  blood  supply  to  that  area  will  be  cut  off,  the 
tissue  will  necrose,  and  the  result  ^dll  be  what  we  know  as  a  gumma. 

The  same  state  of  affairs  may  occur  in  the  basilar  artery,  or  in  any  of  its 
branches,  right  up  to  a  terminal  branch  in  the  cortex.  A  gumma  may  occur,  and 
more  than  one,  if  more  than  one  branch  is  affected,  and  that  in  any  part  of  the  brain 
substance. 

An  exactly  analogous  condition  may  occur  in  the  cord,  and  this  would  appear 
to  be  an  explanation  of  many  phenomena  which  have  hitherto  remained  obscure. 
The  analogy  between  nerve  and  cutaneous  lesions  now  ceases,  although  we  have 
other  conditions  in  the  former  which  require  explanation. 

The  brain  and  cord  are  surrounded  by  meninges.  The  skin  has  no  external 
covering,  and  as  the  meninges  are  infected  when  the  leucocytozoon  becomes 
generalised,  and  as  in  some  places  they  are  in  juxtaposition  to  the  nerve  matter, 
it  will  at  once  be  seen  that,  theoretically,  a  spread  of  the  organisms  from  the  former 
into  the  latter  may  take  place.     The  organisms  reach  the  meninges  via  the  blood 


216 


THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   SYPHILIS. 


stream  ;   therefore,  should  they  ultimately  invade  nerve  tissue,  the  lesion  resulting 
will  be  of  haematogeneous  and  not  of  lymphogeneous  origin. 

From  the  foregoing  it  would  be  justifiable  to  classify  syphilitic  diseases  of  the 
nervous  system  into  two  classes  :  (a)  meningeal ;  {b)  ameningeal,  and  here  a  list 
is  appended. 


Beaix. 


Meningeal 


Ameningeal 


I  !  I 

Dura  Piaarachnoid        Puie  arteiial 

I  i   .     ..  I      .. 

Pachymeningitis  Leptomeningitis        Endarteritis 

(hemiplegia) 


Gumma 


Gumma 


Meningo-encephalitis 
Degenerative  encephalitis  (G.P.I.) 


Arteiial  with  involvement 
of  nerve  substance 


I 


Encephalitis        Gumma        Degenerative 

encephalitis 
(G.PI.) 


Cord. 


Meningeal 

Pure 

End 
(par; 

Ameningeal 

Du 

:'hym 

ra 

iuingitis 

nma       . 

Piaarachnoid 

1 
Leptomeningitis 

Gumma 
-myelitis 

1 
arterial 

1 
irteiitis 
iplegia) 

Arterial  wit 
of  nerve 

h  ini 
subs 

-olveinent 
tance. 

GllE 

My 

jlitis        Gui 

Qiua 

Degenerative 
myelitis  (tabes) 

Meningo 

1 

Atrophic 
muscular 

Latei'al 
sclerosis 

Degenerative  myelitis  (tabes) 

paralyses 

Degen 
myelitis 

;rative 
(tabes) 

i' 

By  adopting  the  above  nomenclature,  such  terms  as  parasyphiUs  and  metaluetic 
lesions  of  the  central  nervous  system  could  be  discarded.  The  term  parenchymatous 
lesion  would  not  be  required,  as  it  only  means  a  lesion  of  nerve  substance,  and  does 
not  denote  whether  the  lesion  was  primarilv  nervous  or  primarily  meningeal. 

Although  the  table  separates  the  brain  from  the  cord,  it  must  be  remembered 
that  clinically  there  is  no  separation,  and  that  many  case.«,  originally  degenerative 
myelitis,  may  end  in  degenerative  encephaUtis. 

Summary. — An    analogy  exists    between  the  infection  of  the  skin  and  the 


THE    BIOLOGY    OF    SYPHILIS    OF   THE    NERVOUS    SYSTEM.  217 

infection  of  the  nervous  system,  and  again  between  the  brain  and  the  cord  lesions. 
The  skin  infection  is  an  haematogenous  one,  and  so  is  the  infection  of  the  nervous 
system.  The  organisms  may  develop  outside  the  vessels,  and  produce  degenerative 
lesions,  such  lesions  being  ameniugeal.  In  most  cases,  the  organisms  reach  the 
nerve  tissue  by  an  exten.sion  from  the  meninges,  and  they  get  into  the  posterior 
part  of  the  cord  more  readily  than  into  the  anterior  part,  because  of  the  septum 
posticum,  which  conveys  the  blood  vessels  into  the  posterior  part  of  the  cord. 

Pure  arterial  lesions  affect  the  anterior  part  of  the  cord  and  are  analogous  to 
those  arterial  lesions,  which  affect  the  base  of  the  brain.  In  other  words,  transverse 
myelitis  is  analogous  to  hemiplegia,  and  degenerative  myelitis  of  the  posterior 
part  of  the  cord  to  degenerative  encephalitis  of  the  cortex  of  the  brain.  Degenerative 
lesions  may  also  occur  in  any  part  of  the  cord  or  brain,  and  are  due  to  the  phases 
of  the  Leucocytozoon  sypMlidis  spreading  perijsherally  from  the  vessel  in  which 
they  developed,  and  to  the  fact  that,  if  the  spread  is  in  grey  matter,  the  spirochaetae 
develop  very  rapidly  extracellularly,  and  cause  marked  local  destruction  of  the 
nerve  cells. 

(c.)  Influence   of  Treatment  upon  the  Incidence   of  Syphilitic  Nervous 

Affections. 

Curiously  enough,  the  influence  of  treatment  upon  the  incidence  of  syphilitic 
nervous  afiections  has  never  heretofore  been  considered.  A  more  important  chapter 
in  syphilis  than  this,  does  not,  in  my  opinion,  exist.  I  trust  it  will  not  be  long  before 
the  profession  at  large  takes  the  matter  into  very  careful  consideration,  as  I  have 
no  doubt  myself  but  that  nervous  symptoms  are  very  rapidly  on  the  increase,  and, 
as  this  view  is  a  rather  disquieting  one,  it  would  be  as  well  to  go  as  fully  as  possible 
into  this  question. 

Two  facts  must  first  of  all  be  borne  in  mind  :  one  is,  that  the  organisms  reach 
the  nervous  system  at  about  the  same  time  as  the  so-called  secondary  rash  appears, 
and  that  all  future  trouble  dates  from  this  invasion.  The  other  is,  that  such  an 
invasion  occurs  in  at  least  70  per  cent,  of  all  cases.  As,  to  all  intents  and  purposes, 
there  is  no  communication  between  the  blood  and  the  cerebro-spinal  fluid,  the 
body,  for  sake  of  argument,  may  be  divided  into — (a)  the  systemic  portion  ;  (b) 
the  nervous  portion. 

In  the  blood,  or,  rather,  in  the  serum,  the  natural  protective  substances  of 
the  host  circulate.  These  natural  protective  substances  are  lipoid-globulins,  and 
have  their  origin  in  lymphocytes,  which  are  again  mainly  manufactured  in  the 
lymphatic  glands.  Broadly  speaking,  there  is  no  limit  to  the  production  of  these 
protective  substances. 


218  THE   BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT    OF   SYPHILIS. 

Although  the  blood  from  the  systemic  portion  circulates  in  the  nervous 
portion,  the  individual  cells  of  the  latter  are  not  bathed  with  it  in  the  same  way  as 
is  the  case  in  the  former.  When  there  is  a  nervous  lesion,  the  protective  substances 
circulating  in  the  blood  do  not  enter  the  cerebro-spinal  fluid,  in  which  circulates 
the  main  supply  of  protective  substances  to  nerve  tissue.  Protective  substances 
can  enter  the  blood  only  from  the  cerebro-spinal  fluid,  and  the  cerebro-spinal  fluid 
is  the  fluid  supply,  so  to  speak,  of  nervous  tissue.  The  reagin  which  circulates  in 
the  cerebro-spinal  fluid  can  enter  the  blood  stream,  and  this  is  the  partial  explana- 
tion of  the  positive  Wassermann  reaction  which  is  obtained  in  the  blood,  in  cases 
of  degenerative  encephalitis  and  degenerative  myelitis. 

Hence,  if  there  is  a  lesion  of  nerve  tissue  proper — i.e.,  apart  from  the  meninges 
— the  main  supply  of  protective  substances  reaches  it  vid  the  cerebro-spinal  fluid. 
Those  circulating  in  the  blood  are  nevertheless  useful.  The  protective  substances 
in  the  cerebro-spinal  fluid  come  mainly  from  the  epithelial  cells  of  the  choroid 
plexuses,  the  supply  of  which  bears  no  relative  proportion  to  that  from  the  lymphatic 
glands  ;  and  partly  the}^  come  from  the  lymphocytes,  which  constitute  the  lympho- 
cytosis, and  these  in  their  turn  come  from  the  lymphatic  vessels  of  the  meninges 
and  nerve  tissue.  Not  all  cases  of  syphilis  show  symptoms  during  the  stage  of  the 
generalisation  of  the  virus,  but  most  do  so.  This  is  perfectly  true  of  the  majority 
of  the  70  per  cent,  of  cases  in  which  the  generalisation  has  reached  the  nervous 
system. 

If  every  physician  will  from  henceforth  examine  very  carefully  the  nervous 
system  of  all  his  cases  of  early  syphilis,  he  will  be  surprised  at  the  very  high  per- 
centage which  show  symptoms.  The  symptoms  are  slight,  but  unmistakable,  and 
are  usually  of  this  nature  : — 

Inequality  of  pupils,  irregularit}'  of  the  pupil  reflexes,  disturbances  in  the 
cranial  nerves,  altered  elbow  and  radial  reflexes,  unequal  abdominal  and  cremaster 
reflexes,  exaggerated  knee-jerks  on  one  or  both  sides,  faint  alterations  in  cutaneous 
sensations,  etc. 

With  and  without  treatment,  the  rule  is  for  all  the  early  symptoms  of'syphUis 
to  disappear  spontaneously.  Treatment  naturally  aids  their  disappearance,  as  it 
increases  the  production  and  efficacy  of  the  protective  substances,  or,  as  they  may 
be  called  for  short,  antibodies. 

Owing  to  the  comparative  weakness  of  the  protective  substances  in  the  cerebro- 
spinal fluid,  the  host  is  partly  dependent  upon  those  circulating  in  his  blood,  to 
overthrow  the  organisms  in  his  central  nervous  system. 

As  substances  cannot  reach  the  cerebro-spinal  fluid  vid  the  blood  stream,  it 
will  be  easily  understood  that  treatment  given  by  the  mouth,  skin,  muscle,  or  vein 


THE    BIOLOGY   OF   SYPHILIS    OF   THE    NERVOUS    SYSTEM.  219 

is  only  going  to  reach  the  nervous  tissue  in  infinitesimal  doses.  Therefore,  the 
steriUsation  of  the  systemic  portion  will  be  achieved  long  before  that  of  the  nervous 
portion. 

If  the  systemic  portion  is  sterilised  early  in  the  disease,  the  production  of 
antibodies  is  checked,  hence  an  important  supply  to  the  nervous  part  is  cut  off, 
at  a  time  when  it  is  most  needed.  The  result  is,  that  the  organisms  may  get  the 
upper  hand,  and  may  give  rise  to  serious  symptoms. 

From  what  has  just  been  stated,  it  will  be  readily  seen  what  a  close  connection 
there  is  between  treatment  and  the  occurrence  of  nervous  lesions. 

For  the  sake  of  clearness,  treatment  may  be  divided  into  three  heads,  and 
every  patient  will  be  regarded  as  a  possible  candidate  for  a  nervous  affection. 

1.  Treatment  by  mercury  alone. 

Sterilisation  of  the  systenr  by  mercury  only  is  a  long  process,  hence  it  will  be 
a  matter  of  years  before  the  supply  of  systemic  antibodies  to  the  nervous  part  is 
cut  off.  The  supply  to  the  nervous  part  may  prevent  the  spores  of  the  Leuco- 
cytozoon  syphilidis  from  developing  into  their  gametal  forms,  but  it  will  not  prevent 
them  from  extending.  The  spores  ■will  extend  from  the  meninges  into  the  cord  and 
brain.  Should  the  supply  of  antibodies  be  cut  off  when  the  spores  have  reached  thi 
cord  and  brain,  the  spores  mil  develop  in  situ,  and  will  cause  degenerative  myelitis  and 
degenerative  encephalitis.  The  more  thorough  and  the  more  drastic  the  mercurial 
treatment  is,  the  quicker  and  more  perfect  the  stoppage  of  the  supply  of  antibodies 
to  the  nervous  system  vnW  be,  therefore  the  greater  likelihood  of  degenerative 
myelitis  and  encephalitis  arising,  and  the  more  meningeal  in  charactt'^'  tlie  early 
symptoms  will  be. 

As  I  have  frequently  stated,  it  is  not  the  untreated  cases  which  are  more  liable 
to  develop  a  degenerative  affection  ;  it  is  those  which  have  been  well  treated  with 
mercury.  In  more  than  75  per  cent,  of  the  cases  of  nerve  degeneration  of  which 
I  have  notes,  the  mercurial  treatment  has  been  severer  than  either  Fournier  or 
Hutchinson  would  have  advised  in  their  time. 

2.  Spasmodic  or  inadequate  treatment  by  salvarsan,  supplemented  or  not 
with  mercury. 

Although,  one,  two,  or  three  injections  of  salvarsan  will  not,  strictly  speaking, 
sterilise  the  system,  the  sterilisation  being  only  pro  tempore,  they  will  stop  the 
manuiacture  of  antibodies.  The  spores  may  be  still  in  the  meninges,  or  may  be 
on  the  point  of  entering  the  nerve  tissue,  hence  the  symptoms  will  be  mainly 
meningeal.  In  the  majority  of  cases,  these  symptoms  are  so  slight  that,  unless  an 
exhaustive  exanrination  be  made,  nothing  is  detected. 

Since  I  have  made  it  the  rule  to  run  over  the  nervous  system  in  every  syphilitic 


220  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

patient,  and  to  test  the  cerebro-spinal  fluid  of  everj^  ease  in  which  my  examination 
leads  me  to  suspect  some  mischief,  I  have  been  surprised  by  the  enormous  number 
of  cases  which  have  marked  evidence  of  imphcation  of  the  nervous  system.  Time 
is  3'et  too  young  to  say  what  the  future  of  these  cases  will  be. 

3.  Several  injections  of  salvarsan,  given  as  closely  after  one  another  as 
possible,  and  followed  by  mercury  for  two  years.  Such  a  treatment  is  usually  able 
not  only  to  sterilise  the  systemic  part,  but  to  sterilise  the  nervous  part  as  well. 

If,  on  the  other  hand,  the  sterilisation  of  the  latter  is  not  complete,  the  check 
on  the  production  of  antibodies  has  been  so  quick  and  sudden,  that  the  spores  will 
develop  rapidly  and  early.  Early  development  of  the  spores  means  that  it  will 
take  place  in  the  meninges.  Rapid  development  signifies  that  the  symptoms  will 
be  severe,  and  therefore  noticeable. 

Consequently,  these  cases  are  purely  meningeal,  easily  diagnosed,  and,  being 
meningeal,  can  be  cured  (\\ith  reserve)  by  further  drastic  treatment. 

These  views  are  not  hypothetical,  but  \'iews  which  I  have  been  forced  to  hold 
from  my  clinical  experience  of  several  hundreds  of  cases. 

There  are  several  other  factors  which  come  into  play  in  the  causation  of  nervous 
lesions,  such  as  the  resistance  of  the  host,  the  protective  power  of  the  cerebro-spinal 
fluid,  the  \nrulence  of  the  infection,  and  the  inter^^al  which  is  allowed  to  elapse 
between  the  commencement  of  the  generalisation  of  the  virus  and  the  inauguration 
of  the  treatment.  Also,  it  must  not  be  forgotten  that  spontaneous  cure  plays  a 
great  part  in  syphilitic  nervous  affections. 

To  make  the  subject  still  clearer,  a  brief  discussion  of  these  various  points  will 
not  be  out  of  place. 

The  resistance  of  the  host  plays  an  important  role  in  this  respect.  The  reader 
has  doubtless  often  heard  the  remark  made,  that,  in  many  cases  of  degenerative 
encephalitis  and  myelitis,  either  no  history  of  s}'philis  could  be  obtained,  or  that 
the  primary  stage  and  stage  of  the  generalisation  were  slight.  The  remark  is 
perfectly  true,  and  its  explanation  is,  in  my  opinion,  the  following : — 

When  such  a  patient  is  infected,  the  generalisation  of  the  virus  tal^s  place, 
but  symptoms  do  not  appear,  owing  to  the  patient's  natural  protective  power  being 
above  the  normal.  As  time  goes  on,  this  naturally  high  protective  power  will  succeed 
in  annihilating  all  the  organisms  in  the  systemic  portion,  with  the  result  that 
the  formation  of  antibodies  will  be  checked. 

The  organisms  have  meanwhile  been  resting  in  the  nervous  portion,  where 
they  do  not  come  under  the  influence  of  this  naturally  increased  protective  power 
to  the  same  extent,  consequently  they  have  sufficient  life  in  them  to  spread.  A 
peripheral  spread  of  the  organisms  in  the  nervous  portion,  always  means  a  spread 


THE    BIOLOGY    OF   SYPHILIS    OF   THE    NERVOUS    SYSTEM.  221 

into  nerve  tissue  proper,  and,  the  further  the  spread  into  nerve  tissue,  the  less 
the  influence  the  natural  protective  capacity  of  the  host  has  upon  them.  Deduct 
from  this  the  power  systemic  antibodies  would  have,  as  by  this  time  they  will  have 
ceased  to  exist,  and  there  is  very  little  to  check  a  widespread  and  active  development 
of  the  organisms.  The  cerebro-spinal  fluid  is  not  itself  strong  enough  to  vanquish 
the  organisms,  as,  by  this  time,  one  has  to  counterbalance  its  action  with  the 
wonderful  medium  nerve  cells  form,  for  the  organisms  to  develop  upon,  hence  de- 
generative encephalitis  and  m3'elitis  result.  Here  I  shoidd  like  to  point  out  a 
very  important  clinical  observation.  A  patient  who,  during  the  latent  stage,  gives 
a  persistently  positive  Wassermann  reaction  of  the  blood,  stands  little  chance 
of  getting  a  degenerative  nerve  lesion  ;  while  a  patient,  who  during  this  stage  gives 
a  persistently  negative  Wassermann  reaction,  is  far  more  likely  to  develop  a 
degenerative  nerve  lesion. 

Therefore,  I  have  for  some  time  made  the  rule  not  to  treat  a  patient  who 
persistently  gives  a  positive  Wassermann  reaction  during  the  latent  stage,  i.e., 
provided  his  previous  treatment  has  been  adequate,  because  I  regard  such  a 
reaction  as  an  indication  of  his  protective  capacity,  which  I  am  only  likely  to 
damage  by  treatment. 

On  the  other  hand,  I  do  not  treat  the  opposite  case  until  I  have  satisfied 
myself  that  a  persistently  negatiVe  Wassermann  reaction  does  not  indicate  that 
the  patient  is  cured.  A  cure  can  be  best  ascertained  by  giving  a  provocative 
injection  of  salvarsan,  or,  better,  by  testing  the  cerebro-spinal  fluid. 

Cases  which  have  very  bad  symptoms,  dm'ing  the  generalisation  stage,  are  very 
prone  to  develop  acute  meningo-encephalitis  and  myelitis.  Severe  symptoms  in 
the  systemic  portion  call  forth  an  abundance  of  antibodies,  and  the  greater  the  call 
upon  antibodies  the  more  persistent  their  production,  and  not  only  that,  the 
production  continues  in  spite  of  the  destruction  of  the  organisms.  Severe  symptoms 
in  the  nervous  portion  call  forth  an  abundance  of  antibodies,  which  raise  the 
protective  capacity  of  the  cerebro-spinal  fluid.  The  result  is,  that  once  the  active 
organisms — i.e.,  those  which  cause  the  symptoms  in  hand — are  vanquished,  the 
spores  are  unable  to  spread,  owing  to  the  powerful  protective  bodies  circulating  in 
both  the  blood  and  in  the  cerebro-spinal  fluid,  consequently  degenerative  encephalitis 
and  myelitis  do  not  follow. 

From  what  has  already  been  stated,  the  reader  can  easily  argue  out  for  himself 
the  influence  which  the  interval,  allowed  to  elapse  between  the  commencement 
of  the  generalisation  of  the  virus  and  the  inauguration  of  the  treatment,  has  upon 
the  incidence  of  syphilitic  nervous  manifestations. 

Broadly  speaking,  the  earlier  treatment  is  commenced  in  the  generalisation 


222  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   SYPHILIS. 

stage,  the  greater  the  likelihood  of  the  nervous  lesions  being  meningeal  in  character, 
and  therefore  being  earlier  in  appearing.  The  later  treatment  is  commenced,  the 
greater  the  likelihood  of  the  nervous  lesions  being  degenerative,  and  therefore 
being  later  in  appearing.  Naturally,  the  kind  of  treatment,  the  kind  of  case,  and 
all  the  other  points  which  have  been  discussed  will  exert  their  influence  in  each 
individual  case. 

Spontaneous  cure  is  a  factor  always  to  be  reckoned  with,  although  it  is  one 
which  does  not  lend  itself  to  discussion.  Spontaneous  cure  naturally  depends 
upon  the  protective  capacity  of  the  antibodies  which  circulate  in  the  blood 
stream  and  in  the  cerebro-spinal  fluid,  hence  one  would  expect  spontaneous  cure 
most  readily  to  follow  true  cases  of  meningitis  This  we  know  clinically  to  be 
the  case. 

It  is  a  well-known  fact  that  many  cases  of  degenerative  myelitis  are 
spontaneously  cured,  but  it  has  not  previously  been  pointed  out,  that  it  is  in  the 
meningeal  form  that  a  spontaneous  cure  is  most  likely  to  occur. 

The  same  with  degenerative  encephalitis.  It  is  in  the  degenerative  meningo- 
encephalitis that  periods  of  quiescence  are  most  common,  while,  in  the  ameningeal 
form,  death  frequently  terminates  the  fii'st  attack. 

The  reason  is  obvious.  In  the  meningeal  lesions,  the  organisms  are  not  living 
upon  a  particularly  luxuriant  medium,  and  they  are  more  open  to  attack  from  the 
protective  bodies,  both  in  the  blood  and  in  the  cerebro-spinal  fluid. 

In  the  ameningeal  lesions,  the  organisms  are  living  upon  a  particularly 
luxuriant  medium,  and  they  are  only  open  to  attack  from  the  protective  bodies 
in  the  cerebro-spinal  fluid. 

The  moral  of  this  nervous  discussion  is  clearly  that  no  treatment,  however 
perfect  it  may  be,  which  is  begun  only  after  the  commencement  of  the  generalisation 
of  the  Leucocijtozoon  syfhilidis,  is  an  absolute  guarantee  of  a  cure.  For  a  cure  to 
be  guaranteed,  the  treatment  must  be  prescribed  before  the  organisms  have  reached 
the  nervous  part.  This  necessitates  an  early  diagnosis  of  the  primary  lesion,  and 
brings  me  to  say  once  more,  that  patients  should  be  urged  to  come  up  for  trsatment 
sooner  than  they  are  now  accustomed  to  do,  that  there  should  be  sufficient  men 
scattered  about  the  United  Kingdom  who  know  what  a  sore  is,  when  they  see  one ; 
as  the  reader  w^  have  learnt  ere  this,  that  a  bacteriological  examination  of  a  sore 
is  not  quite  so  satisfactory  as  it  is  frequently  stated  to  be. 

As  the  clinical  condition  of  haemorrhagic  encephalitis  has  come  into  prominence 
since  salvarsan  has  been  in  use,  and  is  largely  dependent  upon  this  drug,  it  should 
now  be  considered. 

In  some  early  cases  of  s}'3)hilis,  no  skin  lesions  are  to  be  seen,  until  salvarsan 


THE    BIOLOGY    OF   SYPHILIS    OF   THE    NERVOUS    SYSTEM.  223 

has  been  given,  when  either  diffuse  boiled-lobster-coloui-like   blotches   occur,  or 
small  areas  of  redness,  simulating  a  pronounced  roseola. 

Such  lesions  disappear  rapidly,  and  a  histological  examination  of  them  shows 
nothing  more  than  an  unusual  dilatation  of  the  vessels.  No  cellular  infiltration 
is  to  be  found,  and  often  the  section  appears  to  be  normal.  In  the  brain,  an  exactly 
analogous  condition  is  to  be  found,  in  the  so-called  haemorrhagic  encephalitis. 

Now,  haemorrhagic  encephalitis  has  received  special  significance  of  late, 
because  it  has  occurred  somewhat  frequently,  and  usually  ^nth  fatal  results,  after 
the  administration  of  salvarsan. 

Haemorrhagic  encephalitis  may  occur  as  a  syphilitic  symptom,  and  may  end 
fatally,  before  any  treatment  has  been  prescribed.  I  have  had  such  a  case,  and,  histo- 
logically, all  that  I  could  find  were  dilated  vessels  in  the  cortex,  small  haemorrhages 
from  them,  without  there  being  any  very  marked  cellular  infiltration  around  them. 
The  pons  showed  the  greatest  changes.  Therefore  the  condition  may  occur 
independently  of  salvarsan. 

The  erythema  on  the  skin  may  also  follow  mercury  when  it  is  first  given, 
therefore  the  erythema  need  not  necessarily  be  due  to  salvarsan.  The  fatal  cases 
of  haemorrhagic  encephalitis  following  salvarsan  have  always  occurred  in  syphilitic 
patients,  most  commonly  after  the  second  injection  had  been  given — usually  on  the 
third  day — and  in  patients  who  were  in  the  early  generalisation  stage  of  syphilis. 

I  had  one  case,  soon  after  salvarsan  first  came  into  use. 

Case  37. — A  man,  aged  23,  consulted  me  for  syphilis  which  he  had  contracted 
three  months  previously.  His  symptoms,  upon  examination,  consisted  of  a  maculo- 
papular  rash,  and  iritis  of  the  left  eye.  No  organic  disease  in  the  \'iscera  was 
discernible,  and  there  was  no  albmnin  in  the  urine. 

After  the  second  intravenous  injection  of  "  006,"  which  was  given  eight  days 
after  the  first,  the  patient  complained  of  headache.  Suddenly,  during  the  evening 
of  the  third  day,  he  had  an  epileptic  fit  of  Jacksonian  type.  He  soon  went  into 
the  condition  of  Status  epilepticus,  in  which  he  died  a  few  hours  later.  Neither 
after  the  first  nor  the  second  injection  was  there  any  albumin  in  the  urine. 

Post-mortem,  the  only  macroscopic  change  to  be  noticed  was  an  arachnoid 
cyst  over  the  right  rolandic  area.  Microscopic  examination  showed  that  the 
meningitis  was  of  some  years  duration,  and  that  there  was  no  recent  inflammation, 
although  syphilis  had  been  contracted  only  three  months  previouslv.  The  nerve 
cells  of  the  cortex  underneath  the  cyst'  had  undergone  marked  plasmolysis.  Their 
shape  was  altered,  and  no  NissFs  granules  were  discernible.  Elsewhere  the  vessels 
of  the  cortex  appeared  to  be  dilated ;  there  was  no  extrusion  of  blood,  and  there 
was  no  perivascular  cellular  infiltration. 

p 


224  THE    BIOLOGY,    CLINICAL    ASPECT   AND    TREATMENT   OF    SYPHILIS. 

There  can  be  no  doubt  but  that  this  was  a  case  of  haemorrhagic  encephahtis, 
which  started  as  an  epileptic  fit  of  Jacksonian  type,  o\^-ing  to  the  old  arachnoid 
cyst,  which  proved  an  area  of  minor  resistentiae. 

The  arachnoid  cyst  was  probably  due  to  an  accident  which  the  patient  had 
had  years  before,  but  no  history  was  obtainable  upon  this  point.  The  patient 
was  always  morose,  and  none  of  his  relations  or  friends  knew  much  about  him. 

There  are  degrees  of  haemorrhagic  encephalitis,  because,  in  some  cases,  no 
macroscopic  or  microscopic  changes  are  to  be  found  in  the  cerebral  cortex.  In 
some  cases,  merely  a  dilatation  of  the  vessels  is  all  that  is  to  be  seen ;  in  some, 
the  dilatation  of  the  vessels  is  very  severe,  with  the  result  that  they  are  sur- 
rounded by  extravasated  blood,  and  in  one  case  I  examined,  which  occurred 
independently  of  salvarsan,  there  was  in  addition  some  perivascular 
cellular  infiltration.  In  another  case,  the  perivascular  cellular  infiltration  was 
very  marked. 

As  to  the  direct  cause  of  the  condition,  difierent  opinions  prevail.  The  fact 
that  it  occurs  most  commonly  after  the  second  injection  of  salvarsan,  early  in  the 
generalisation  stage  of  syphilis,  suggests  the  following  to  my  mind  : — 

Early  in  the  generalisation  stage,  the  body  has  not  yet  become  accustomed  either 
to  the  s\T)hiUtic  organisms,  or  to  the  toxines  which  would  naturallv  result  upon  their 
destruction. 

The  patient  can  probably  stand  the  first  toxic  dose  he  gets,  but  succumbs  to 
the  second,  which  acts  as  an  anaphylotoxine.  The  anaphylotoxine  paralyses  the 
vasoconstrictors.  Hence  the  dilatation  of  the  vessels,  extravasation  of  blood,  and 
oedema  of  the  brain. 

Why  should  the  symptoms  not  arise  until  the  third  day  ? 

If  a  drug  is  given  intravenously,  we  know  that  it  reaches  the  skin  more  quickly, 
and  in  greater  quantities  than  it  reaches  the  cortex  of  the  brain. 

The  erythema,  following  salvarsan,  sets  in  often  twenty-four  hours  or  more 
after  the  injection  has  been  given.  If  the  drug  readies  the  brain  more  slowly,  and 
in  smaller  quantities,  it  would  take  more  than  twenty-fom'  hours  for  the 
anaphylotoxine  to  be  formed — possibly  seventy-two  hours,  i.e.,  the  third  day. 

It  is  undoubtedly  on  the  third  day,  'that  the  reactionary  inflammation 
surrounding  intracranial  lesions  is  most  marked.  I  had  a  patient  with  syphilitic 
pachymeningitis,  who  became  unconscious  on  the  third  day  after  the  second 
injection,  due  to  the  reactionary  inflammation  having  raised  the  intracranial 
pressure  so  as  to  cause  compression.  Lumbar  puncture  was  followed  by  immediate 
rehef. 

Ehrlich^  is  of  the  opinion  that  the  condition  is  partly  due  to  the  toxic  action 


THE    BIOLOGY   OF   SYPHILIS   OF   THE   NERVOUS    SYSTEM.  225 

of  an  oxidation  product  of  salvarsan,  namely,  paramiuophenylarsenoxide,  and  that 
symptoms  do  not  appear  until  the  third  day,  which  is  the  time  required  for  the 
oxidation  product  to  be  formed. 

The  following  facts,  to  my  mind,  rather  point  against  Ehrlich's  conception, 
since  haemorrhagic  encephalitis  may  occur  independently  of  treatment,  because  it 
is  analogous  to  the  cutaneous  erythema  which  may  follo^\  mercury,  because  it  is 
commoner  after  salvarsan  than  after  neo-salvarsan,  while  the  latter  oxydises  very 
much  more  quickly  than  the  former.  It  is  not  quite  such  an  active  spirillocide, 
hence  the  amount  of  anaphylotoxine  formed,  following  the  use  of  neo-salvarsan, 
would  be  less  than  that  formed  from  the  use  of  salvarsan. 

The  formation  of  paraminophenylarsenoxide  is  favoured  by  all  forces  which 
cause  a  delay  in  salvarsan  excretion,  such  as  an  overdose,  or  presence  of  kidney 
disease.  Under  these  conditions,  larger  quantities  of  salvarsan  than  usual  may 
remain  behind  in  the  body,  and  succumb  later  to  oxidation,  forming  the  dangerous 
oxide.  These  are  extra  explanations  which  Ehrlich  brings  forward  in  favour  of  his 
hypothesis. 

Many  of  the  cases  which  have  been  reported  have  not  had  overdoses,  and  in 
many  there  was  no  kidney  disease. 

If  the  question  of  kidney  disease  came  in,  it  is  difficult  to  see  why  Encephalitis 
haemorrhagica  does  not  occur  in  the  cases  of  late  syphilitic  nervous  diseases,  when 
the  kidney  is  sometimes  diseased,  when  the  nervous  tissue  is  far  below  par,  and 
when  several  injections  of  salvarsan  are  given. 

Under  these  circumstances,  haemorrhagic  encephalitis  does  not  occur,  because 
the  patient  is  immune  to  the  toxine  formed  from  the  death  of  the  organisms,  some 
of  which  doubtless  have  been  killed  daily  for  months  or  years.  In  lesions,  where 
there  are  myriads  of  spLrochaetae  present,  such  as  in  some  cases  of  degenerative 
encephalitis,  their  destruction  leads  to  such  a  big  dose  of  toxine  that  the  patient 
quickly  succumbs. 

Another  interesting  point  which  now  crops  up,  is  the  question  as  to  whether 
the  kidney  is  diseased — because  of  syphilis — in  the  early  generalisation  stage  of 
the  disease. 

The  occurrence  of  protein  in  the  urine  in  early  sj'philis  is  no  proof  that  the 
kidney  is  diseased. 

In  many  cases,  the  so-called  albuminuria  in  generalised  syphilis  is  not  due  to 
albumin.  It  may  be  due  to  globulin,  or  to  a  lipoid-globulin,  which  is  merely  excreted 
through  the  kidneys  from  the  blood,  because  the  serum  can  hold  no  more. 

Ehrlich  further  considers  that  a  third  factor  comes  into  play,  namely,  the 
insufficient  quantities  of  adrenalin  in  the  blood,  as  would  occur  in  Addison's  disease. 

p2 


226  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF    SYPHILIS. 

So  far  as  we  know,  the  suprarenals  are  not  afiected  by  syphilis  in  the  early 
stages  of  the  disease,  therefore  it  is  unhkely  that  this  factor  plays  a  great  role. 

There  is  no  doubt,  as  Mihan  *  ^  has  ingeniouslv  shown,  that  tbe  administration 
of  adrenalin  will  often  combat  unpleasant  symptoms  following  salvarsan,  such  as  blue- 
red  swelling  of  the  face,  lips,  dyspnoea,  etc.,  severe  diarrhoea,  and  suppression  of 
urine. 

Milian,  by  means  of  energetic  adrenalin  treatment,  saved  an  otherwise  hopeless 
case  of  Encephalitis  haemorrhagica  in  which,  after  the  second  salvarsan  injection,  the 
deepest  coma  ensued. 

Adrenalin  doubtless  overcomes  the  vasodilation  effect  of  the  anaphylotoxine, 
and  this  is  probably  its  action  in  these  cases. 

There  seems  no  justification  for  assuming  that  these  vasodilatator  phenomena 
arise  because  there  is  less  adrenahn  circulating  in  the  blood  at  the  time. 

There  is  some  deeper  reason  for  haemorrhagic  encephalitis  than  its  mere 
occurrence  after  salvarsan.  Haemorrhagic  encephalitis  is  a  syphilitic  lesion,  and 
it  may  occur  in  any  stage  of  syphilis,  although  it  is  extremely  rare  after  the  third 
year  following  the  infection.  The  earlier  the  case,  the  more  truly  haemorrhagic 
the  lesion  is,  but,  as  a  rule,  if  the  condition  occurs  independently  of  treatment,  the 
dilated  vessels  are  generally  surroimded  by  a  l}anphoc3rtic,  and,  in  some  cases,  by 
a  mixed  lymphocytic  and  plasma-celled  infiltration. 

I  have  had  one  case  occurring  after  salvarsan,  in  which  there  was  no  perivascular 
cellular  infiltration  ;  two  cases,  which  occurred  independently  of  treatment,  in 
which  there  was  a  marked  perivascular  infiltration  ;  and  one  case  which  occurred 
seven  years  after  infection.  This  last  case  is  one  of  the  most  interesting  I  have 
ever  seen,  as  it  throws  considerable  light  upon  many  points,  which  I  am  attempting 
to  emphasise  in  the  chapters  on  s}^hilis  of  the  nervous  system. 

Case  38. — The  patient,  a  man,  aged  32,  contracted  syphihs  seven  years  pre- 
viously, and  he  was  treated  with  mercury  internally  for  about  three  years.  One 
year  before  I  saw  him  he  had  complained  of  severe  pains  in  his  legs,  bladder  trouble 
developed,  and  the  patient  became  slightly  ataxic.  In  this  condition  he  "svas  seen 
by  two  physicians,  who  diagnosed  the  condition  as  tabes.  He  was  then  given 
two  intramuscular  injections  of  salvarsan,  with  the  result  that  his  symptoms 
practically  vanished.  A  few  months  after  the  salvarsan  had  been  prescribed,  the 
patient  developed  very  bad  headaches,  he  lost  his  memory,  he  took  a  very  long  time 
to  answer  questions,  and  became  very  quiet,  apathetic,  but  not  irritable.  Three 
days  after  definite  sjonptoms  of  cerebral  trouble  had  manifested  themselves,  the 
patient  became  comatose,  and  a  week  later  he  died,  in  spite  of  every  effort  made 
to  save  him. 


THE    BIOLOGY   OF   SYPHILIS    OF   THE   NERVOUS    SYSTEM.  227 

Post-mortem,  the  meninges  and  cortex  of  the  brain  were  markedly  inflamed, 
histologically,  one  fomid  a  dilatation  of  the  cortical  vessels,  with  a  pronounced 
lymphocytic  and  plasma-celled  infiltration  surrounding  them  ;  here  and  there 
there  had  been  extravasations  of  blood.  The  changes  were  well  marked  in  the 
pons,  into  which  there  had  also  been  several  haemorrhages,  but,  in  every  area  in 
which  a  haemorrhage  had  taken  place,  there  was  a  pronounced  cellular  infiltration. 

The  interesting  points  about  this  case  are,  first,  that  the  nervous  symptoms 
were  primarily  spinal ;  these  cleared  up,  and  then  the  patient  died  with  cerebral 
symptoms.  Secondly,  the  cerebral  symptoms  did  not  develop  until  treatment 
had  been  prescribed.  Similar  symptoms  to  the  above,  only  very  much  milder, 
although  the  patient  may  become  actually  comatose,  are  not  at  all  uncommon 
after  treatment,  in  cases  of  encephalitis  and  meningo-encephalitis. 

As  a  rule,  the  coma  develops  on  the  third  day  after  the  second  injection  of 
salvarsan.  Active  continuance  of  the  treatment  cures  the  patient,  but  it  failed  to 
do  so  in  the  case  just  described,  because  the  condition  had  occurred  some  time  after 
the  treatment  had  been  given,  and  was  therefore  more  due  to  the  disease  itself 
than  to  the  treatment ;  and  it  also  failed  because  the  active  treatment  was  not 
prescribed  soon  enough. 

This  case  fully  proves  the  statement  made  some  pages  back,  that  unless  the 
treatment  of  a  nervous  lesion  be  drastic,  it  is  better  not  to  prescribe  salvarsan  or 
neo-salvarsan  at  all. 

/SMmmary.— Treatment  has  a  very  decided  influence  upon  the  outbreak  of 
nervous  symptoms.  The  development  of  the  organisms  in  the  central  nervous 
system  is  kept  in  check,  both  by  the  cerebro-spinal  fluid  and  bj^  the  antibodies 
which  circulate  in  the  blood  stream.  Treatment  exerts  its  influence  by  checking 
the  production  of  systemic  bodies,  and  thus  deprives  the  central  nervous  system  of 
one  of  its  protective  arms.  The  more  quickly  the  systemic  antibodies  are  destroyed 
the  earlier  the  onset  of  nervous  symptoms,  and  vice  versa ;  i.e.,  provided  the 
treatment  is  first  prescribed  in  the  generalisation  stage.  The  earlier  the  onset  of 
nervous  symptoms,  the  more  meningeal,  and  the  later  their  onset,  the  more 
degenerative  in  character  they  will  be.  Hence,  the  more  drastic  the  early  treat- 
ment is,  the  better  the  prognosis,  should  nervous  symptoms  arise,  since  meningeal 
lesions  are  easier  to  cure  than  degenerative  ones.  Moreover,  early  drastic  treat- 
ment destroys  all  the  organisms  in  the  walls  of  the  blood  vessels,  with  the  result 
that  ameningeal  nervous  lesions  will  be  rare. 

To  avoid  the  onset  of  any  nervous  symptoms  at  all,  treatment  must  be  pre- 
scribed before  the  patient  enters  the  generalisation  stage. 

Haemorrhagic  encephalititis,  occurring  in  syphilis,  is  always  primarily  due  to 


228  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   SYPHILIS. 

the  disease,  but  its  onset  may  be  influenced  by  treatment,  and  may  be  produced 
by  the  spirochaetal  toxine.     The  condition  is  never  due  to  saJvarsan. 


{(!)    Other  Factors  Which  Play  a  role  in  the  Causation  of  Syphilitic 

Nervous  Lesions. 

Having  described  how  syphihs  attacks  the  nervous  system,  it  might  be  as  well 
to  see  it  there  are  any  other  factors,  which  come  into  play  in  its  causation. 

Although  no  actual  statistics  exist  as  to  the  prevalence  of  acquired  nerve 
syphilis,  I  do  not  think  one  would  be  far  wrong  in  saying  that  about  10  per  cent,  of 
patients  who  contract  sj-philis,  develop  a  marked  central  nervous  system  lesion. 

Although,  personally,  I  think  the  percentage  is  on  the  increase,  which  is  contrary 
to  the  view  generally  held,  I  feel  still  more  certain  that  in  a  few  more  years  the 
percentages  will  be  greater  still,  owing  to  the  indiscriminate  and  inadequate 
manner  in  which  the  new  arsenic  preparations  have  been  prescribed. 

We  are  now  certain  that,  in  at  least  60  per  cent,  of  cases  of  syphilis, 
the  organisms  reach  the  nervous  system,  i.e.,  including  the  meninges,  very  early 
in  the  stage  of  the  generalisation  of  the  virus.  In  fact,  it  may  be  possible  to  obtain 
a  lymphocytosis  in  the  cerebro-spinal  fluid  before  the  Wassermann  reaction  in  the 
blood  is  positive. 

If  in  as  many  as  60  per  cent,  of  cases  the  organisms  reach  the  nervous  system, 
why  do  only  so  few  develop  symptoms  later  ? 

The  local  protective  power  of  the  host,  the  antibodies  circulating  in  the  blood 
system,  the  amount  of  treatment,  and  the  time  at  which  it  is  begun,  are  all  factors 
which  influence  the  destruction  of  the  organism. 

Do  those  organisms  which  remain,  and  give  rise  to  symptoms,  do  so  because 
they  have  a  special  neurotropic  action,  or  because  the  patient  has  a  neuropathic 
disposition  ? 

Affirmative  e\'idence  for  both  suggestions  has  frequently  been  brought  forward. 
In  favour  of  the  neurotropic  action  of  the  organism  is  the  fact,  that  cases  have  been 
described  in  which  two  or  more  individuals — not  blood  relations — have  been 
infected  Irom  the  same  source,  and  have  developed  a  degenerative  lesion  later. 

In  favour  of  the  neuropathic  disposition  is  the  fact,  that  degenerative  ence- 
phalitis is  most  likely  to  affect  those  whose  brains  have  been  severely  taxed  by 
worry,  etc.,  and  also  individuals  who  have  had  their  resistance  lowered  by  alcohol, 
which  acts  as  a  poison,  especially  upon  the  brain  cortex. 

Difierent  poisons  which  have  a  neurotropic  action,  the  area  involved  is  very 
seldom  the  same. 


THE    BIOLOGY   OF    SYPHILIS    OF   THE    NERVOUS    SYSTEM.  229 

The  diphtheria  toxiji3  has  a  predilection  for  certain  nerves  ;  tubercle  and 
alcohol  seldom  affect  the  cord.  Ergot  favours  the  posterior  columns.  Lead  picks 
out  special  peripheral  nerves,  such  as  the  nuisculospiral,  and,  oddly  enough,  that 
musculospiral  belonging  to  the  arm  which  does  the  most  work  is  most  frequently 
affected,  a  neuropathic  phenomenon. 

Although  the  biology  of  s3'philitic  central  nervous  system  lesions  can  be 
explained  on  other  lines,  it  would  appear  at  present,  that  the  neurotropic  action  of 
the  organism  and  the  neuropathic  disposition  of  the  individual  played  some  role. 

Taking  all  the  evidence  we  have,  we  ought  to  be  able  to  throw  more  light  upon 
the  nature  of  the  syphilitic  lesions  affecting  the  central  nervous  system.  If  there 
was  anything  in  the  neurotropic  action  of  a  certain  strain  of  the  specific  organism, 
many  more  cases  would  have  been  described.  Think  of  the  thousands  of  cases  of 
degenerative  myelitis  and  encephalitis  there  have  been,  so  that  the  few  described, 
as  pointing  to  a  neurotropic  action  of  the  organism,  may  safely  be  regarded  as 
coincidences. 

Weygandt  and  Jakob^  proved  experimentally  that,  if  they  infected  rabbits  with 
a  neurotropic  strain  of  organism,  that  is,  a  strain  that  had  already  produced  nervous 
symptoms,  no  more  developed  nervous  lesions  than  rabbits  which  had  been 
infected  with  a  non-neurotropic  strain.  The  neuropathic  disposition  is  merely 
another  expression  of  the  locus  minor  resistentiae.  Against  the  neurotropic  action 
and  neuropathic  disposition,  is  the  fact  that  parasyphilitic  affections  of  the  nervous 
system  are  rare,  and  in  many  cases  unknown,  in  spite  of  the  fact  that  syphilis  is 
very  common  in  Turkey,  Persia,  Egypt,  Algiers,  Abyssinia,  China,  and  in  certain 
parts  of  Africa,  where  often  more  than  70  per  cent,  of  the  natives  have  syphilis. 
Moreover,  the  natives  who  have  contracted  the  disease  have  been  infected  by 
white  men,  many  of  whom  develop  a  degenerative  lesion  later. 

The  reason  why  these  natives  do  not  suffer  from  late  nervous  lesions  is,  in  my 
opinion,  due  to  the  fact  that  they  are  so  badly  treated  that  a  period  seldom  arises 
in  which  the  antibodies  in  the  systemic  part  are  absent,  therefore,  what  organisms 
there  are  in  the  nervous  part  are  kept  at  bay. 

It  will  be  seen  readily,  from  what  I  have  stated,  how  much  the  development  of 
the  organisms  in  the  nervous  s^'stem  is  influenced  bj'  treatment. 

Since  most  patients  are  not  treated  until  the  leucocytozoon  has  reached  the 
nervous  system,  if  the  treatment  is  quick  and  sivre,  should  nervous  symptoms  arise, 
they  will  be  those  of  pure  meningeal  syphilis ;  if  the  treatment  is  slow  but  sure, 
should  symptoms  arise,  they  will  be  degenerative  ones.  If  the  treatment  is  bad, 
then  nervous  symptoms  will  be  less  likely  to  arise. 

By  slow  and  sm-e  treatment,  I  would  mean  treatment  with  one  or  two  injections 


230  THE    BIOLOGY,    CLINICAL    ASPECT   AND   TREATMENT    OF   SYPHILIS. 

of  salvarsan,  and  mercurial  injections  given  intermittently  for  two  or  three  years. 
By  the  bad  treatment,  I  would  mean  treatment  by  pills  only. 

Since  the  treatment  has  been  passing  from  the  bad  into  the  slow  and  sure, 
there  has  been  a  steady  increase  in  the  so-called  parasyphilitic  affections.  This 
has  been  proved  to  me,  apart  from  my  own  personal  experience,  by  a  letter  sent 
by  Professor  Wimmer,  of  Copenhagen,  in  which  he  clearly  indicates  that  the 
percentage  of  cases  with  nervous  lesions  is  gradually  going  up,  year  by  year ;  and 
by  several  talks  with  Mr.  Shillitoe,  who,  from  his  notes  of  cases  of  syphilis  which 
have  been  through  his  and  his  father's  hands  during  the  last  fifty  years,  is  sure 
that  many  more  patients  are  developing  degenerative  lesions  than  used  to  do  so. 

When  we  come  to  discuss  the  selective  influence  of  different  organisms  for 
different  nerve  paths,  we  immediately  run  against  an  impenetrable  wall,  since 
absolutely  nothing  is  known  about  it  at  present. 

"Who  can  answer,  why  should  the  virus  of  anterior  poliomyelitis  pick  out  for 
preference  those  nerve  cells  situated  in  the  anterior  horns  ? 

So  far  as  syphilis  is  concerned,  I  can  see  no  evidence  for  assuming  that  the 
leucocytozoon  has  any  selective  action,  and  the  reason  why  posterior  column  lesions 
should  be  so  much  more  common  than  anterior  horn  lesions,  can,  I  think,  be  readily 
explained  on  anatomical  grounds. 

Late  lesions  of  the  brain  need  not  necessarily  be  those  of  degenerative  ence- 
phalitis— gummata,  for  instance,  may  occur.  The  reason  why,  in  the  one  case,  it  is 
degenerative  encephalitis,  and  in  the  other  a  gumma,  is  explained  by  Mackintosh 
and  Fildes'  on  the  hy3)ersensitiveness  theory.  As  already  stated,  the  cause  of 
hypersensitiveness  is  not  known,  and,  moreover,  why  degenerative  encephalitis 
or  a  gumma  should  arise,  can  be  easily  explained  on  anatomical  grounds,  and  by 
the  manner  in  which  the  organism  develops  ;  whether  it  develops  in  the  walls  of  the 
vessels  or  outside  them. 

1  Weygandt  u.  Jakob  (1914),  "  Dermat.  Wochensclirf."     Festschrift,  150. 

°  Orr  and  Rows  (1914),  "  Proc.  Roy.  Soc.  of  Med."     vii,  (Psych.  Sect.),  21.  , 

3  Erhlich  (1914),  "  Brit.  Med.  Journ."  i,  1044. 

••  MiHan  (1913),  "  Bull,  de  !a  Soo.  Franc,  de  Derm,  et  de  Syph.,"  xxiv,  272. 

"■  Ibid.  (1914),  .,  „  „  „  XXV,  231. 

«  Macnamara  (1913),  "  Lancet,"  ii,  385. 

'  Mackintosh  and  Fildes  (1914).     "  Brain,"  xxxvii,  141, 


CHAPTER  XXIV. 
THE  CLINICAL  ASPECT  OF  SYPHILIS  OF  THE  NERVOUS  SYSTEM. 

It  is  not  my  intention  to  describe  in  full  the  symptoms  of  the  syphilitic  nervous 
lesions,  because  the  reader  could  be  better  informed  by  consulting  a  textbook  on 
nervous  diseases. 

All  I  propose  to  do,  is  to  draw  attention  to  the  chief  signs  and  symptoms  of 
each  of  the  lesions  mentioned  in  the  table  in  Chapter  XXIII,  with  which  a 
syphilologist  is  most  likely  to  be  confronted. 

Before  dealing  with  the  central  nervous  system,  a  few  words  must  be  said 
about  syphilis  of  the  peripheral  nerves. 

Syphilitic  neuritis  may  be  single  or  multiple.  The  lesion,  when  one  nerve  is 
affected,  is  usually  to  be  found  in  its  distal  part,  while,  in  those  cases  in  which  more 
than  one  nerve  is  involved,  the  lesion  or  lesions  are  either  in  the  plexus  itself,  or 
the  case  is  one  of  a  root  neuritis.  The  so-called  syphilitic  polyneuritis,  which  is 
only  met  ^vith  in  the  generalisation  stage,  is  a  peripheral  neuritis,  and  is  probably  due 
partly  to  the  presence  of  the  organisms  themselves  in  the  endo-  and  perineurium, 
and  partly  to  the  toxines  which  are  elaborated  by  the  death  of  the  spirochaetae 
in  situ.  That  the  neuritis  is  most  probably  partly  a  toxic  neuritis,  is  proved  by  the 
fact  that,  in  nearly  all  cases  of  syphilitic  polyneuritis,  the  patient  has  had  mercurial 
treatment.  Because  of  this  fact,  it  has  been  frequently  maintained  that  the  poly- 
neuritis under  discussion  was  a  neuritis  due  to  mercurial  poisoning.  This  is  certainly 
not  the  case,  because  if  mercury  is  pushed  in  such  a  case,  or  salvarsan  is  prescribed, 
all  the  symptoms  disappear. 

The  most  common  nerve  to  be  affected,  when  the  neuritis  is  single,  excluding 
the  cranial  nerves,  is  the  sciatic  nerve,  but  it  must  be  remembered  that  neuritis 
of  the  sciatic  nerve  is  not  infrequently  secondary  to  a  syphilitic  lesion  in  the  neigh- 
bourhood. It  may  be  secondary  to  a  gumma  in  a  muscle,  or  to  a  periostitis  of  the 
ischium.  It  depends  upon  the  position  of  the  inflammation,  whether  the  motor 
part  is  more  involved  than  the  sensory  part,  or  vice  versa. 

Treatment  in  these  cases  should  be  begun  as  quickly  as  possible,  so  as  to  prevent 


232  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

the  fibrous  tissue  contraction  from  causing    degeneration  of  some  of  the  nerve 
fibres. 

If  fibrous  tissue  contraction  and  degeneration  have  set  in  before  treatment  is 
prescribed,  it  may  be  a  matter  of  weeks  before  the  patient  is  relieved,  and  even 
after  drastic  salvarsan  treatment,  pains  may  still  persist.  In  all  cases  of  peripheral 
neuritis  not  of  syphilitic  origin,  the  administration  of  salvarsan  is  bound  to  aggravate 
the  symptoms  in  increasing  ratio,  as  the  number  of  the  injections  is  raised  ;  hence 
this  form  of  aggravation  can  be  differentiated  from  that  of  reactionary  inflam- 
mation, which  only  follows  the  first  two,  or,  at  most,  three  injections.  In  s;^'philitic 
neuritis  of  the  sciatic  nerve,  the  sensory  fibres  are  more  often  affected  than  the 
motor  fibres.  If  the  neuritis  is  mainly  a  motor  neuritis,  the  chances  are  that  the 
inflammation  is  in  the  sciatic  plexus,  and  if  only  one  motor  nerve  is  affected,  and 
it  is  most  often  the  peroneal,  it  is  to  be  feared  that  the  lesion  may  be  central. 

The  brachial  plexus  is,  in  my  experience,  the  plexus  most  frequently  affected, 
and  the  side  I  have  seen  involved  has  always  been  the  right.  It  is  characteristic 
for  a  syphilitic  plexus  neuritis  to  be  unilateral.  When  the  condition  is  bilateral, 
it  is  almost  certain  that  the  patient  has  a  root  nem-itis,  or,  in  other  words,  a  cer^acal 
pachymeningitis. 

In  the  cases  of  brachial  neuritis  which  I  have  seen,  the  motor  disturbance  has 
always  been  greater  than  the  sensory  disturbance,  while,  in  two  cases  of  root 
neuritis  I  have  had  under  my  care,  the  sensory  signs  were  more  pronounced  than 
the  motor  signs.  In  both  of  my  cases  of  root  neuritis,  the  cerebro-spinal  fluid 
was  markedly  pathological,  and  indicated  a  meningitis  :  while  in  one  of  my  cases 
of  brachial  neuritis,  the  cerebro-spinal  fluid  was  normal.  In  both  the  cases  of  root 
neuritis  referred  to,  the  upper  extremities  were  much  more  involved  than  the  lower  ones. 

Both  plexus  neuritis  and  root  neuritis  do  excellently  under  treatment  with 
salvarsan,  but  in  the  case  of  the  latter,  if  a  cure  is  to  be  hoped  for,  several  intrathecal 
injections  of  salvarsanised  serum  have  to  be  given. 

Poll/neuritis  syphilitica  is  most  commonly  to  be  met  with  in  the  generalisation 
stage,  while  the  other  forms  just  described  generally  occur  round  about  the  fourth 
year  and  later,  seldom  earlier. 

We  now  have  to  consider  neuritis  of  the  cranial  nerves,  but  lesions  of  the  cranial 
nerves,  which  occur  in  syphilis,  should  be  discussed  from  a  different  standpoint. 
The  lesions  may  be  di%-ided  into  two  classes  :   {a)  secondary  ;   {b)  primary. 

Lesions  of  Secondary  Origin. 
Xeuro-recurrences  come  under  this  heading,  but  they  are  fully  discussed  else- 
where {vide  Chapter  XXVIII).     The  lesions  which  have  not  so  far  been  mentioned 


THE    CLINICAL   ASPECT   OF   SYPHILIS    OF   THE   NERVOUS    SYSTEM.  233 

are  those  which  occur  in  syphilitic  basal  meningitis  (leptomeningitis).  The 
following  cases  are  good  examples  : — 

Basal  Meningitis.  Case  39. — A  man,  aged  40  years,  developed  syphilis  eleven 
years  previously,  but  as  he  had  no  other  symptoms  but  the  sore,  he  only  took 
mercury  internally  for  six  months.  In  1908,  gummata  developed  in  the  skin,  and 
some  of  the  cranial  nerves  became  involved.  Some  improvement  was  obtained, 
after  several  injections  of  soamin,  and  potassium  iodide  internally.  In  January, 
1910,  he  had  diplopia,  and  was  much  troubled  with  headache  and  vomiting.  In 
March,  1910,  he  first  noticed  weakness  of  the  right  side  of  the  face,  and  was  treated 
with  mercury  and  iodide,  with  only  temporary  improvement.  When  seen  on 
September  12th  of  the  same  year,  the  condition  was  as  follows  : — "  There  is  an 
internal  strabismus  with  diplopia,  due  to  paralj^sis  of  the  right  external  rectus 
and  weakness  of  the  left  external  rectus.  The  movements  of  the  eye  dependent 
on  the  third  nerve  are  good.  The  pupils  react  well,  and  the  vision  is  good.  There 
is  some  swelling  of  both  optic  disks.  There  is  paralysis  of  the  right  side  of  the 
face,  and  both  motor  and  sensory  portions  of  the  right  fifth  nerve  are  involved. 
There  is  deafness  on  the  right  side,  but  the  tuning-fork  is  audible  when  placed  in 
contact  with  the  mastoid.  There  is  some  unsteadiness  in  gait,  but  this  would 
seem  to  be  dependent  on  the  diplopia.  Rhomberg's  sign  is  absent,  and  there  is 
no  weakness  of  the  limbs.  The  knee-jerks  are  active  and  equal  :  the  plantar 
reflex  cannot  be  obtained,  and  the  abdominal  reflexes  are  difficult  to  elicit, 
but  they  are  equal.  The  articulation  is  somewhat  nasal,  but  no  weakness 
of  the  palate  can  be  detected,  although  there  is  some  difiiculty  in  deglutition.  The 
movements  of  the  tongue  are  good.  It  seems  probable  that  there  is  a  circumscribed 
syphilitic  meningitis  at  the  base  of  the  brain,  involving  the  right  fifth,  sixth,  and 
seventh  cranial  nerves,  and  probably  also  the  right  eighth  and  ninth,  and  the  left 
sixth  to  a  lesser  degree.  There  is  no  evidence  of  any  affection  of  the  p}T:amidal  tracts. '' 
An  intramuscular  injection  of  0'.5  grm.  of  "  606  "  was  given.  The  patient  was  very 
ill  for  a  few  days,  but  on  the  third  day  the  temperature  returned  to  normal,  and  he 
declared  that  his  hearing  had  improved.  Within  a  week  he  could  walk  without  a 
stick,  all  the  affected  nerves  had  regained  some  of  their  power,  the  improvement  in 
the  sixth  and  seventh  being  very  striking.  The  injection  was  given  on  Sep- 
tember 12th,  and  on  September  28th  the  following  letter  was  received  from 
Mr.  Hare  under  whose  care  the  patient  then  came  : — 

"  Optic  neuritis  is  still  present,  but  the  patient  says  his  visual  power  has 
improved  daily,  especially  during  the  last  four  or  five  days.  The  third,  fourth, 
fifth,  sixth,  and  seventh  nerves  all  show  signs  of  improvement  in  fimction,  but  I 
cannot  find  any  increase  of  hearing  on  the  right  side,  though  the  patient  says  there 


234  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT    OF    SYPHILIS. 

is.  Swallowing,  respiration,  and  heart's  action  all  improved.  To-day  the  heart 
beat  was  perfectly  regular  at  78,  whereas  I  have  often  found  marked  irregularity 
both  as  regards  rate  and  strength." 

Another  letter,  dated  October  12th,  states  that  the  optic  neimtis  has  almost 
gone,  the  eyesight  greatly  improved,  and  that  the  patient  can  walk  100  yards  without 
staggering.     The  hearing  has  also  greatly  improved. 

In  this  last  case,  although  there  was  no  return  of  symptoms,  the  patient  had 
an  idea  that  a  further  injection  would  possibly  aid  in  completely  getting  rid  of  those 
that  remained  ;  consequently  a  second  was  given,  with  dire  results.  Soon  after  the 
injection  he  became  cyanosed,  and  had  great  difficulty  in  breathing  ;  this  as  well  as 
another  similar  attack  passed  oft',  but  they  were  followed  on  the  third  day  by  another, 
which  proved  fatal. 

This  case  is  exceedingly  instructive,  because,  in  all  intracranial  afiections,  this 
difficulty  in  breathing  is  not  uncommon,  especially  after  an  intramuscular  injection. 

The  dyspnoea  is  undoubtedly  due  to  a  further  raising  of  the  intracranial 
pressure,  caused  by  reactionary  inflammation  around  the  diseased  focus,  which 
inhibits  the  respiratory  centre. 

Should  such  a  thing  occur,  either  a  lumbar  puncture  should  be  resorted  to,  or 
the  skull  should  be  opened.     In  any  case,  adrenalin  injections  should  be  given. 

Cerebrospinal  Meningitis. — It  is  impossible  to  say  where  cerebral  sj'philis 
ends  and  cerebro-spinal  syphilis  begins,  since  the  meninges,  vessels,  etc.,  of  the 
brain  and  spinal  cord  are  continuous ;  and,  although  a  case  may  have  symptoms 
only  of  cerebral  syphilis,  post-mortem  examination  may  reveal  changes  in  the 
meninges  of  the  cord,  and  ince  versa. 

For  instance,  a  man  came  up  complaining  of  headaches,  insomnia,  and  double 
vision,  five  years  after  infection.  He  had  lately  become  so  depressed  and  irritable, 
that  he  was  on  the  point  of  giving  up  his  work  in  the  city.  The  double  vision,  due 
to  paresis  of  one  third  nerve,  was  accompanied  by  paresis  of  the  facial  on  the  same 
side.  Both  would  be  present  for  a  few  weeks,  then  disappear,  to  become  evident 
again  later.  Pupils  unequal,  R.  >  L.  Right  reflexes  gone,  left  weak,  disks 
normal.  Patellar  reflexes  gone.  Wassermann  reaction  in  blood  negative,  but  in 
cerebro-spinal  fluid  positive,  positive  lymphocytosis,  and  phase  I.  Mercurial  in- 
unctions soon  stopped  the  double  vision,  but,  no  sooner  had  the  patient  finished  a 
course,  than  the  paresis  again  appeared. 

In  October,  1910,  patient  had  an  intramuscular  injection  of  "  606  "  during 
an  attack  of  facial  paralysis  and  double  vision,  which  disappeared  within  a  few 
days,  the  headaches  and  insomnia,  vanished,  and  the  patient  felt  no  longer  depressed 
or  unable  to  work.     Both  the  pupil  and  patellar  reflexes  reappeared. 


THE   CLINICAL  ASPECT   OF   SYPHILIS   OF  THE  NERVOUS   SYSTEM.  235 

Case  40.— A  married  woman,  aged  47,  whose  infection  occurred  probably  twenty- 
four  years  ago,  and  who,  after  her  second  marriage,  had  five  consecutive  miscarriages. 
Nervous  symptoms  began  in  1901,  when  the  left  arm  and  leg  were  noticed  to  drag, 
and  there  was  giddiness,  with  disturbance  of  vision — in  the  patient's  words,  "  things 
went  suddenly  black."  She  was  admitted  into  the  Great  Northern  Hospital  for 
seven  weeks.  Four  years  later,  she  complained  of  partial  paralysis  of  the  left  arm 
and  leg,  cramps  in  both  legs,  double  vision,  and  loss  of  memory  for  minor  events. 
This  time  she  was  admitted  into  King's  College  Hospital  for  sixteen  weeks,  and 
left  much  better.  A  year  later,  she  was  re-admitted  for  eleven  weeks,  because  she 
had  occasional  attacks  of  imconsciousness,  during  which  she  squinted.  Dui'ing  the 
past  year,  there  were  further  attacks  of  faintness  and  giddiness,  which  have  been 
very  much  worse  for  the  past  three  months.  Three  weeks  ago,  she  dropped  down 
unconscious  in  the  street ;  since  then  she  has  complained  of  continual  dizziness 
and  headache,  and  a  marked  tendency  to  fall  to  the  right  side  when  walking.  On 
admission  she  had  double  optic  neuritis  ;  the  right  pupil  was  smaller  than  the  left, 
but  both  reacted  to  light  and  accommodation.  There  was  paralysis  of  both 
external  recti,  paresis  of  the  lower  half  of  the  left  side  of  the  face,  and  deafness  on 
the  right  side.  The  patient  could  not  hear  a  watch  held  within  an  inch  of  the  ear, 
nor  when  it  was  placed  on  the  temporal  bone  ;  the  tongue  was  protruded  to  the 
right,  the  other  cranial  nerves  were  normal.  Muscular  power  and  sensation  in  the 
arms  was  good  and  equal,  tendon  reflexes  increased,  there  was  inco-ordination. 
In  the  legs,  muscular  power  and  sensation  were  good  and  equal  on  both  sides.  Knee- 
jerks  present  and  equal,  no  clonus,  plantars  brisk  and  flexor,  co-ordination  impaired  ; 
other  systems  normal. 

On  October  24th  patient  had  an  injection  of  "  606."  On  October  26th  the 
paralysis  of  the  external  recti  had  completely  disappeared,  and  there  was  less 
headache  ;  inco-ordination  was  less,  the  hearing  on  the  right  side  had  improved 
to  the  extent  of  hearing  a  watch  held  within  one  inch  of  the  ear.  The  paresis  of 
the  lower  half  of  the  left  side  of  the  face,  and  the  protrusion  of  the  tongue  to  the 
left  were  still  present.  By  November  8th,  the  facial  paralysis  had  almost  dis- 
appeared, the  tongue  was  protruded  in  the  middle  line,  and  when  the  patient 
walked  about  the  ward  it  was  noticed  that  there  was  no  tendency  to  fall  to  either  side. 
When  she  left,  on  November  16th,  one  would  not  have  known  that  there  had  been 
anything  the  matter  with  her. 

Mr.  Etherington  Smith  examined  the  case  on  January  24th,  and  kindly  sent 
me  the  following  note  : — 

"  Her  improvement  has  been  maintained,  and  she  has  now  no  symptoms  at 
all ;   the  optic  neuritis  has  gone,  leaving,  of  course,  post-neuritic  changes,  and  the 


236  THE    BI0L0C4y,    CLINICAL   ASPECT   AND    TREATMENT   OF    SYPHILIS. 

vessels  are  markedly  degenerate.  She  lias  slight  facial  weakness  on  the  left  side, 
but  all  the  other  paralyses  are  gone.  The  left  pupil  reacts  fairly  well,  the  right  is 
small  and  does  not,  which  is  probably  due  to  old  posterior  synechiae.  She  now  does 
all  her  ordinary  work." 

Instead  of  the  process  spreading  anteriorly,  as  it  usually  does,  it  may  spread 
posteriorly,  and  involve  the  last  cranial  nerves,  but  fortunately  syphilitic  bulbar 
paralysis  is  rare. 

Another  fairly  common  secondary  lesion  is  one  which  gives  rise  to  a  sudden 
diplopia.  The  nerve  most  frequentlj^  affected  is  the  third  nerve,  and  the  paralysis 
is  due  to  a  thrombosis  of  one  of  the  arterial  supplies  to  that  nerve. 

The  double  vision  comes  on  instantaneously.  Often  the  patient  wakes  up 
in  the  morning  to  find  the  defect.  Frequently  the  paralysis  is  preceded  by  head- 
ache. In  almost  every  case,  only  one  branch  of  the  oculomotor  nerve  is  involved. 
The  patient  is  generally  over  50  years  of  age,  and  the  condition  clears  up  under 
appropriate  treatment,  but  it  is,  one  might  say,  invariably  the  signal  for  a  more 
extensive  thrombosis  at  a  later  date.  Within  the  last  four  years,  I  have  seen  three 
cases.  In  all  the  cases,  the  patients  died  T\'ithin  three  years  from  hemiplegia,  with 
extensive  haemorrhage. 

Lesions  of  Primary  Origin. 

These  are  natm'ally  lesions  which  commence  in  the  nerves  themselves  or  in 
their  nuclei,  hence  they  are  degenerative  in  nature.  Curiously  enough,  it  is  nearly 
always  the  eye  nerves  that  are  affected.  Primary  optic  atrophy  is  the  example 
of  the  second  cranial  nerve. 

Primary  optic  atrophy  is  always  bilateral,  but  the  sight  in  one  eye  is  usually 
better  than  that  in  the  other.  In  most  cases,  it  is  a  matter  of  years  before  the 
patient  becomes  bhnd,  and  even  then  the  blindness  may  not  be  absolute.  The 
condition  is  almost  always  accompanied  by  a  degenerative  myelitis,  but  there  are 
one  or  two  rather  interesting  points  about  the  ty|)e  of  the  myelitis. 

The  signs  and  symptoms  of  the  degenerative  myelitis  are  not,  as'  a  rule, 
pronounced  ;  indeed,  they  may  be  missed,  unless  the  patient  is  examined  carefully. 
As  a  rule  the  knee-jerks  are  gone,  and  the  patient  may  have  a  slight  ataxia,  but 
lightning  pains  are  generally  absent.  Another  very  interesting  point,  is  that  in 
some  cases  the  signs  and  symptoms  of  the  degenerative  myelitis  vanish  when  the 
optic  atrophy  appears.  I  may  say  that  I  have  never  seen  a  case  of  optic 
atrophy  accompanied  by  a  very  pronounced  or  severe  degenerative  myelitis. 
Statements  have  been  made  that,  if  treatment  is  sufficiently  early  prescribed,  the 
course  of  the  atrophy  will  be  checked,  but  it  must  be  remembered  that,  in  many 


THE    CLINICAL   ASPECT   OF   SYPHILIS   OF   THE    NERVOUS    SYSTEM.  237 

cases,  the  normal  course  is  slow,  eo  that  it  would  be  an  extremely  difl&cult  matter  to 
say  whether  treatment  had  influenced  the  course  or  not.  Nevertheless,  treatment 
is  going  to  do  no  harm.  Salvarsan  will  not  aggravate  the  condition,  therefore 
every  patient  should  be  given  the  chance,  and  treated  vigorously. 

The  other  nerves  commonly  affected  are  the  sixth,  the  third,  and  the  fourth. 

The  diplopia  following  a  lesion  of  any  one  of  these  cranial  nerves  is,  usually,  of 
slow  origin.  Individuals  on  the  rightside  of  forty-five  are  those  most  commonly 
affected,  and  although  the  double  vision  may  disappear  under  treatment,  the 
chances  are  that  the  patient  will  develop  degenerative  myelitis,  and  more  rarely 
encephalitis  later.  The  course  run  by  the  cases  varies  enormously,  but  the 
follo'wing  is  what  most  usually  happens.  The  patient  complains  of  double  \nsion. 
On  examination,  the  external  rectus  is  found  to  be  paralysed  on  one  side.  Under 
treatment  the  paralysis  disappears,  or  it  may  remain  permanently.  If  the  paralysis 
does  disappear,  it  usually  recurs  later,  when  the  lesion  becomes  more  extensive 
and  a  part  of  the  third  nerve  usually  becomes  involved.  In  time,  in  spite  of 
treatment,  all  the  eye  muscles  become  affected,  and  the  patient  ultimately  develops 
bilateral  ophthalmoplegia.  The  trochlear  nerve  may  be  affected  first,  or  the 
oculomotor  nerve  ;  or  ptosis  may  be  the  first  indication  that  a  cranial  nerve  is 
affected.  Unless  treatment  is  started  early,  and  even  in  spite  of  treatment, 
atrophy  of  the  affected  nerve  may  quickly  result.  As  a  rule,  when  the  case 
recurs,  the  paralysis  does  not  disappear  under  treatment.  The  paralysis  of 
the  eye  muscles  generally  precedes  the  degenerative  myelitis,  and  often  when 
the  paralysis  recurs,  signs  and  symptoms  of  the  myelitic  condition  begin.  As 
in  the  case  of  optic  atrophy,  the  degenerative  myelitis  which  follows  is  not  usually 
severe  ;  it  is  of  the  meningeal  type,  and  whether  it  is  only  a  coincidence  or  not  I 
cannot  say,  but,  in  every  case  I  have  seen  in  which  the  paralysis  has  caused  ptosis 
and  affected  many  eye  muscles,  the  patient  has  always  had  gastric  crises.  The  knee- 
jerks  have  been  absent,  the  patients  have  not  been  ataxic  ;  as  a  rule  the  patients 
have  had  areas  of  numbness,  and  every  one  has  lost  his  sexual  power. 

We  will  now  pass  on  to  the  syphilitic  lesions  of  the  brain,  and  discuss  them 
in  the  order  in  which  they  appear  in  the  table  in  Chapter  XXIII. 

Meningeal. 

Pachymeningitis. — A  syphilitic  inflammation  of  the  dura  may  be  either 
generalised  or  localised.  Generalised  pachymeningitis  is  one  of  the  commonest 
symptoms  of  early  syphilis,  and  is  probably  one  of  the  causes  of  the  headaches 
which  are  so  frequently  complained  of  in  the  generalisation  stage.     Chronic  diffuse 


238  THE   BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   SYPHILIS. 

pachymeningitis  is  a  common  cause  of  persistent  headache  in  the  later  stages  of 
syphilis — indeed,  syphilis  should  be  seriously  considered  in  every  patient  over  forty 
who  complains  of  continual  headache.  It  must  also  be  remembered  that  pure 
arterial  lesions  are  also  a  common  cause  of  headaches  in  patients  over  forty,  and  it 
is  highly  probable  that  a  diiJuse  vascular  lesion  is  the  other  cause  of  headaches 
in  early  syphilis.  The  generalised  forms  of  pure  pachymeningitis  do  not  give  rise 
to  any  other  symptoms,  and  do  not  cause  optic  neuritis. 

The  headaches  may  be  situated  anywhere,  but  as  a  rule  they  are  worst  over 
the  vertex  and  at  the  occiput ;  in  fact,  they  are  ofteia  localised  to  one  of  these  two 
areas.  The  pain  does  not  tend  to  shift  about,  and  not  infrequently  a  tender  spot 
is  to  be  felt  when  palpating  the  head.  The  patient  usually  knows  where  it  is,  as 
he  has  frequent  cause  to  touch  it  when  combing  and  brushing  his  hair.  Generalised 
pachymeningitis  responds  almost  instantaneously  to  anti- syphilitic  treatment,  but 
the  form  occurring  in  late  syphilis  is  very  apt  to  recur,  though  never  ^dth  the  same 
severity  as  before  the  initial  treatment  was  prescribed.  As  to  whether  headaches 
are  produced  by  meningeal  or  vascular  lesions,  the  cerebro-spinal  fluid  must  be 
examined  before  a  differential  diagnosis  can  be  made. 

The  locaUsed  pachymeningitis  is  the  Pachymeningitis  gummosa,  symptoms  of 
which  are  indistinguishable  from  those  of  cerebral  tumour.  An  examination  of  the 
cerebro-spinal  fluid  and  watching  the  effect  of  treatment  are  the  only  means  of 
making  a  differential  diagnosis. 

Leptomeningitis. — A  diffuse  syphilitic  inflammation  of  the  dura  is  most  common 
on  the  vertex,  while  a  diffuse  syphilitic  inflammation  of  the  arachnoid  and  pia  is 
most  common  on  the  base.  Leptomeningitis  does  not  cause  headaches.  As  a 
rvile,  it  does  not  give  rise  to  symptoms  till  late  in  the  disease,  when  an  affection  of 
certain  cranial  nerves  calls  one's  attention  to  it,  and  it  frequently  causes  optic 
nem'itis. 

Meningo-encepJuilitis. — The  diagnosis  of  meningo-encephalitis  is  not  a  difficult 
matter,  but  it  is  important  to  ascertain,  as  soon  as  possible,  whether  the  lesion  is 
a  degenerative  one  or  not.  , 

The  meningo-encephalitis  may  be  diffuse  or  localised.  If  diffuse,  besides  the 
headaches  of  which  all  patients  complain,  the  chief  symptom  is  a  progressive 
dementia.  The  patient  is  apathetic.  He  takes  no  interest  in  his  work,  and  his 
memory  deteriorates ;  but  there  is  neither  the  exaltation  nor  the  depression, 
which  are  characteristic  of  the  degenerative  type.  Other  symptoms  are  that  the 
patient  becomes  slovenly  in  his  habits,  and  all  his  movements  are  slow,  and  bis 
reactionary  period  is  lengthened. 

The  pupil  anomalies  are  an  exceedingly  important  and  frequent  symptom. 


THE   CLINICAL   ASPECT   OF   SYPHILIS   OF   THE    NERVOUS    SYSTEM.  239 

The  pupils  maj^  be  equal,  dilated,  but  tlieir  reflexes  sluggish.  On  the  other  hand, 
they  may  be  unequal,  and  the  reflexes  may  be  absent  only  on  the  one  side.  It  is 
because  of  the  pupil  anomalies  that  a  diagnosis  of  degenerative  encephalitis  is 
frequently  made.  If  the  reflexes  of  the  affected  pupil  are  absolutely  lost  before 
treatment  is  commenced,  it  may  generally  be  presumed  that  the  patient  has  a 
degenerative  lesion.  In  a  degenerative  lesion,  tremors  are  more  constant  and 
marked  than  in  a  non-degenerative  lesion.  To  make  absolutely  certain  as  to 
whether  one  is  dealing  with  an  ordinary  case  of  meningo-encephalitis,  or  with  a 
degenerative  one,  the  only  way  is  to  watch  the  effects  of  treatment  upon  the  pupils. 
If  the  reflexes  return,  the  case  belongs  to  the  former  category,  if  they  do  not  return, 
then  the  case  is  a  degenerative  one.  It  must  be  remembered  that  a  degenerative 
meningo-encephalitis  may  begin  as  an  ordinary  case  of  meningo-encephalitis.  The 
age  of  the  patient,  the  time  of  onset  of  the  symptoms  after  the  infection,  and  an 
examination  of  the  cerebro-spinal  fluid,  are  points  which  will  weigh  in  a  properly 
adjusted  balance,  and  cause  either  the  scale  which  represents  the  degenerative 
form,  or  the  other  to  fall. 

Localised  meningo-encephalitis  is  very  seldom  degenerative,  therefore  the 
difficulty  of  mistaking  the  two  does  not  arise.  Jacksonian  epileiDsy  is  a  common 
symptom  of  this  localised  form.  Monoparalyses  and  hemiparalysis  may  be  met 
with.  The  patient  may  have  attacks  of  unilateral  or  localised  paraesthesias,  usually 
accompanied  by  dizziness.  Cortical  speech  disturbances  and  hemianopsia  are  other 
symptoms  which  may  be  encountered. 

When  optic  neuritis  is  met  with  in  meningo-encephalitis,  the  chances  are  in 
favour  of  the  lesion  being  basal  and  not  cortical,  therefore,  in  all  cases  in  which  optic 
neuritis  occurs,  a  thorough  examination  of  the  cranial  nerves  should  be  instituted, 
as  an  affection  of  any  one  of  these  practically  clinches  the  diagnosis  of  a  basal 
meningo-encephalitis.  a  form  of  encephalitis  which  is  practically  never  followed 
by  the  degenerative  form.  Treatment  of  ordinary  meningo-encephalitis  is  always 
followed  by  excellent  results,  and,  if  the  treatment  is  thorough,  the  tendency  to 
recur  is  small. 

Ameningeal. 

Endarteritis. — Endarteritis  may  be  an  early  or  a  late  symptom  of  syphilis. 
In  the  early  stage,  hemiplegia  is  the  commonest  lesion,  and  the  course  of  the  case 
is  nearly  always  of  this  fashion.  The  patient  complains  of  bad  headaches,  which  he 
may  have  had  for  some  days,  or  only  for  a  day  or  two.  With  the  exception  of  the 
headache,  which  may  even  in  some  cases  be  absent,  the  patient  goes  to  bed  feeling 
perfectly  well,  and  wakes  up  in  the  morning,  to  find  himself  paralysed  down  one 

Q 


240  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   SYPHILIS. 

side.  If  treatment  is  commenced  at  once,  the  patient  so  far  recovers  that  an 
expert  would  fail  on  examination  to  discover  that  the  patient  had  ever  had  hemi- 
plegia. If  treatment  is  delayed,  restoration  is  never  complete,  and  there  is  great 
risk  of  contractures,  etc.,  supervening. 

The  great  difference  between  early  and  late  hemiplegia  is  that,  in  the  latter, 
there  is  always  haemorrhage,  which  ultimately  kills  the  patient,  if  not  during  the  first 
attack,  during  a  subsequent  one,  and  the  hemiplegia  is  often  preceded  either 
weeks,  months,  or  years  by  a  small  endarteritic  lesion  elsewhere,  such  as,  for  instance, 
an  ocular  palsy. 

Haemorrhagic  ejicephalitis  and  gumma  have  already  been  described,  and  need 
no  repetition  (tJw/e  Chapter  XXIII. ). 

Degenerative  Encephalitis. — As  has  been  already  seen,  degenerative  encephalitis 
may  be  of  meningeal  or  of  ameningeal  origin.  The  prognosis  of  the  meningeal 
form,  so  far  as  relapses  or  periods  of  quiescence  are  concerned,  is  better  than  in 
the  ameningeal  form,  for  reasons  already  explained. 

Treatment  in  both  forms  is  very  unsatisfactory,  and,  in  the  ameningeal  form, 
usually  results  in  hastening  the  end. 

The  following  case  is  instructive. 

Ca.se  41. — A  man,  aged  39,  contracted  syphilis  in  1896.  He  had  several  primary 
sores,  and  the  usual  symptoms  of  the  generalisation  stage.  He  was  treated  with 
mercurial  inunctions  for  six  months,  and  then  developed  a  right-sided  hemiplegia. 
The  mercurial  inunctions  were  continued,  in  spite  of  the  hemiplegia,  with  the  result 
that,  in  three  days,  the  patient  could  talk  again,  and  in  a  few  more  days  the  power  in 
the  arm  and  leg  returned.  Mercurial  treatment  was  continued  for  over  three  years. 
The  patient  consulted  me  in  Julj^  1914,  because  he  felt  so  fearfully  depressed.  The 
depression  bordered  almost  on  suicidal  mania.  The  pupils  were  unequal,  E.  >  L. 
The  left  pupil  did  not  react  to  light,  but  it  did  to  accommodation,  while  the  right 
pupil  reacted  to  both.  All  the  reflexes  were  exaggerated,  and  the  patient  had 
tremors.  It  should  be  said  that  the  depression  had  set  in,  only  three  months  before 
I  saw  him.  > 

Examination  of  the  cerebro-spinal  fluid:  Pressure  not  raised.  Lymphocytes, 
12  per  c.mm.  Phase  I  feebly  positive.  Wassermann  reaction  positive  in 
1,000  per  cent,  only 

If  any  case  appeared  amenable  to  treatment,  this  one  certainly  did,  so  I  gave 
eight  intraspinal  injections  of  salvarsanised  serum,  the  number  required  to  render  the 
cerebro-spinal  fluid  absolutely  normal.  The  patient  appeared  to  improve  somewhat, 
and  the  reflexes  in  the  left  pupil  were  undoubtedly  brisker  than  they  were  to  start 
with,  but  the  faint  reaction  to  light  only  lasted  for  a  few  days.     A  fortnight  later 


THE   CLINICAL   ASPECT   OF   SYPHILIS   OF   THE   NERVOUS    SYSTEM.  241 

the  patient  suddenly  entered  the  exaltation  stage  ;  a  week  later  he  became  violent, 
he  then  gradually  became  more  and  more  demented,  and  had  to  be  interned  in  an 
asylum. 

I  was  able  to  get  the  cerebro-spinal  fluid  absolutely  normal,  and  yet  the  case 
went  more  and  more  downhill.  From  other  similar  experiences,  I  have  decided 
not  to  prescribe  anti-syphilitic  treatment  in  cases  of  degenerative  encephalitis, 
especially  if  they  are  of  ameningeal  origin. 

A  very  interesting  point,  and  one  which,  to  my  mind,  throws  considerable  light 
upon  the  explanation  of  the  Argjdl-Robertson  pupil,  is  the  fact  that  pupil  anomalies 
are  less  frequent  in  cases  of  degenerative  encephalitis  than  in  cases  of  degenerative 
myelitis.  Since,  moreover,  pupil  anomalies  are  to  be  met  with  in  cases  of  degenera- 
tive encephalitis,  there  nmst  be  some  regulating  factor  of  the  pupil  in  the  cerebral 
cortex. 

Cord. 

Me7iingeal. 

Pachij-  and  Leptomeningitis. — Owing  to  the  fact  that  the  spinal  cord  itself 
does  not  occupy  the  whole  of  the  spinal  space,  symptoms  of  a  spinal  meningitis  are 
not  usually  pronounced  enough  to  cause  the  patient  to  seek  advice.  Furthermore, 
a  spinal  meningitis  is  most  often  a  combined  meningitis,  and  even  if  one  gets  a 
true  pachymeningitis  or  a  true  leptomeningitis,  it  is  not  a  very  simple  matter  to 
difEerentiate  them,  therefore  the  two  forms  will  be  considered  together. 

It  is  said  that  the  meninges  of  the  spinal  cord  are  much  less  frequently  affected 
than  the  meninges  of  the  brain.  This  is  certainly  not  true,  although  it  is  a  fact 
that  cranial  meningitis  is  much  more  frequently  met  with  than  spinal  meningitis, 
for  the  simple  reason  that  an  inflammation  of  the  meninges  of  the  brain  always 
gives  rise  to  symptoms,  while  inflammation  of  the  meninges  of  the  cord  only  gives 
rise  to  symptoms  when  the  inflammation  is  particularly  severe. 

Although,  for  sake  of  convenience,  a  line  is  drawn  between  cranial  and  spinal 
meningitis,  the  reader  must  never  forget  that  a  combined  cerebro-spinal  meningitis 
is  more  common  than  either  a  pure  cranial,  or  a  pure  spinal  lesion. 

In  cerebral  meningitis,  the  meninges  covering  the  cortex  are  more  frequently 
involved  than  those  covering  the  base.  In  the  case  of  the  cord,  this  is  even  still 
more  marked,  as,  in  the  majority  of  cases,  it  is  the  posterior  surface  that  is  affected. 
The  symptoms  are  pains  in  the  neck,  between  the  shoulder  blades,  and  down  the 
back.  Paraesthesias  of  the  extremities,  especially  of  the  legs,  are  commonly  to  be 
met  with.    A  tender  spot  may  be  elicited  on  tapping  the  vertebral  column.     The 


242  THE    BIOLOGY.    CLINICAL    ASPECT    AND   TREATMENT   OF   SYPHILIS. 

tendon  and  skin  reflexes  are  usually  increased.  Symmetrical  analgesia,  or  a 
distui'bance  in  the  temperature  and  touch  senses,  often  occur  as  early  symptoms. 
If  the  symptoms  are  severer  than  those  described,  either  the  meningitis  has  caused 
a  root  neuritis  or  a  myelitis. 

Meningo-myelitis. — This  is  the  form  of  spinal  cord  syphilis  which  is  most 
frequently  encountered,  as  the  symptoms  caused  compel  the  patient  to  seek  advice. 
The  symptoms  are  either  exaggerated  forms  of  those  above  described,  or  they  may 
be  only  slight.  On  this  latter  account,  it  is  by  no  means  always  an  easy  matter 
to  distinguish  between  a  spinal  meningitis  and  a  meningo-myelitis. 

In  undoubted  cases  of  meningo-myelitis,  the  tendon  reflexes  are,  at  any  rate 
at  first,  usuall}'  increased,  but  the  skin  reflexes  are  as  often  diminished  as  they  are 
increased.  Babinski's  and  Oppenheim's  phenomena  are  usually  present,  but  they 
may  be  ascertainable  on  one  side  only. 

A  weakness  of  the  bladder  and  sexual  functions  are  common  symptoms. 

The  symptoms  of  meningo-myelitis  vary,  according  to  the  part  of  the  cord 
affected.  Those  already  described  are  typical  of  an  affection  of  the  dorsal  region, 
the  part  of  the  cord  which  is  most  frequently  involved.  Should  the  meningo- 
myelitis  be  most  marked  in  the  lumbar  region,  the  bladder  and  sexual  symptoms 
come  more  to  the  fore,  and,  as  a  rule,  all  the  reflexes  are  absent.  If,  on  the  other 
hand,  the  inflammation  is  most  pronounced  in  the  cervical  tegion,  the  reflexes  of 
the  upper  extremities  are  altered,  and  the  varied  cutaneous  sensations  are  to  be 
found  in  the  arms.  Owing  to  the  close  connection  between  the  cervical  and 
sympathetic  nei-ves  in  this  region,  pupil  anomalies  are  to  be  met  with,  and  also 
other  signs  of  an  affection  of  the  sj^mpathetic  system.  The  pupil  on  the  affected 
side  is  smaller  than  the  one  on  the  opposite  side.  The  eyeball  may  appear  more 
.sunken,  and  alterations  of  blood  supply  and  sweat  secretion  of  the  face,  on  the 
^affected  side,  may  be  very  noticeable  symptoms. 

If  meningo-myelitis  were  a  distinct  disease,  it  would  not  be  difficult  to  diagnose 
it,  but  as  it  is  in  most  cases  accompanied  by  meningo-encephalitis,  and  as  the 
symptoms  of  the  latter  usually  both  precede  and  are  severer,  or,  better  td  say,  more 
noticeable  than  those  of  the  former,  the  diagnosis  is  complicated.  This  is,  no 
doubt,  the  reason  why  the  term  cerebro-spinal  syphilis  was  given  to  the  combined 
condition. 

Meningo-myelitis  differs  in  no  way  from  meningo-encephalitis,  that  is  to  sa}% 
^;he  case  may  run  an  extremely  acute  course,  and  may  kill  the  patient.  On  the  other 
'hand,  it  may  advance  verj'  slowly,  and  with  the  exception  of  the  very  acute  cases, 
if  treatment  is  prescribed  early  enough,  and  is  sufficiently  drastic,  the  condition  may 
ibe  cured.     If   he  disease  has  progressed  fai-  before  treatment  is  prescribed,  naturally. 


THE   CLINICAL   ASPECT   OF   SYPHILIS    OF   THE    NERVOUS   SYSTEM.  243 

secondary  degeneration  will  ensue,  and  the  case  will  become  one  of  degenerative 
myelitis.  Just  as  it  may  be  difficult  to  differentiate  the  degenerative  from  th& 
non-degenerative  form  of  meningo-encephalitis,  so  may  the  differential  diagnosis  of 
the  two  forms  of  meningo-myelitis  be  by  no  means  an  easy  matter.  Hence  the 
reason  why  we  meet  with  the  term  "  pseudo-tabes  "  in  literature. 

As  both  the  degenerative  and  the  non-degenerative  types  of  meningo-myelitis 
frequently  exist  together,  one  cannot  tell  to  what  extent  the  lesion  is  degenerative 
until  thorough  treatment  has  been  given.  Since  treatment  can  do  no  harm  in  any 
form  of  meningo-m5'elitis,  provided  it  is  not  stopped  too  soon,  every  doubtful  case 
should,  at  least,  be  given  the  chance  of  being  improved  thereby. 

Ameningeal. 

Paraplegia. — Like  hemiplegia,  paraplegia  occurs  in  early  syphilis.  The 
patient  often  wakes  up  to  find  his  legs  paralysed,  and  the  paralysis  is  frecpiently 
preceded  by  acute  pains  down  the  lower  extremities.  Occasionally  the  course  is 
slower,  or  a  transient  paralysis  is  all  that  occurs,  or  only  one  leg  is  paralysed.  When 
only  one  leg  is  paralysed,  the  other  may  follow  suit  at  a  later  date.  If  treatment  is 
prescribed  early,  no  trace  of  the  lesion  is  left  behind.  It  is  frequently  stated  that 
the  condition  is  liable  to  recur.  I  have  seen  many  cases  of  syphilitic  paraplegia, 
but  have  only  notes  of  a  single  case  in  w'hich  the  condition  recurred,  four  years  after 
the  first  attack. 

Transverse  myelitis  is  the  term  usually  applied  to  the  lesion,  but  it  must  be 
remembered  that  there  is  not  in  every  case  an  involvement  of  nerve  substance. 

Besides  the  paralysis,  the  other  symptoms  are,  loss  of  sensation,  increased 
tendon  reflexes,  or  abolished  tendon  reflexes.  If  the  lesion  is  located  in  the  lumbar 
cord,  paralysis  of  the  sphincters  of  the  bladder  and  rectum,  and  oedema  of  the  lower 
extremities,  and  decubitus  are  sometimes  to  be  met  with. 

The  advent  of  transverse  myelitis  may  sometimes  be  anticipated,  before  the 
condition  actually  occurs,  as  the  prodromal  symptoms  may  be  quite  pronounced. 
If  treatment  is  begun  then,  the  onset  of  paralysis  may  be  thwarted. 

The  prodromal  symptoms  can  be  divided  into  sensory,  motor,  and  sphincteric 
disturbances.  The  sensory  symptoms  consist  in  paraesthesias  and  radiating  pains 
down  the  lower  extremities.  Sensitiveness  to  movements  of  the  trunk  is  very 
characteristic,  and  is  a  point  upon  which  Charcot  always  laid  emphasis.  The  motor 
symptoms  consist  in  twitchings  of  the  toes,  feet  or  legs,  with,  maybe,  transient 
palsies  thereof.  Paralysis  of  the  sphincters  may  be  preceded,  as  Williamson  has 
pointed  out,  by  retention. 


244  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   SYPHILIS. 

Arterial  Lesions  with  involvement  of  the  Nerve  Substance. — The  myelitis  may  be 
haemorrhagic  in  character,  analogous  to  haemorrhagic  encephalitis,  and,  like  the 
condition  just  mentioned,  it  generally  has  a  fatal  termination.  I  have  only  had 
one  case  of  this  form  of  myelitis,  and,  in  spite  of  commencing  treatment  at  once  with 
salvarsan,  mercurial  inunctions,  and  potassium  iodide  internally,  the  patient  died. 
Naturally,  there  are  stages  of  haemorrhagic  myelitis,  as  there  are  stages  of 
haemorrhagic  encephalitis.  By  this  I  mean  that  some  cases  are  foudroyant  and 
haemorrhagic  only.  Others,  again,  are  less  acute,  and  death  does  not  take  place 
so  quickly.'  Post-mortem,  instead  of  finding  dilated  vessels  with  extramural 
haemorrhages,  there  is  a  marked  lymphocytic  infiltration — lymphocytic  myelitis. 

In  those  cases  of  myelitis  where  the  involvement  of  the  nerve  substance  is  less 
sudden  and  the  area  is  less,  varied  conditions  may  be  met  with,  such  as  localised 
muscular  paralyses,  the  syphilitic  form  of  Landry's  paralysis,  lateral  sclerosis, 
gumma,  and  degenerative  myelitis  (tabes)  itself. 

Degenerative  myelitis  usually  begins  de  novo,  or  it  may  be  preceded  by  a 
localised  muscular  paralysis,  or  even  by  the  sj'philitic  form  of  Landry's  paralysis. 

Instead  of  one  muscle  being  paralysed,  several  muscles  may  be  paralysed,  with 
the  result  that  a  true  syphilitic  anterior  poliomyelitis  may  be  met. 

Degenerative  Myelitis. — The  name  most  frequently  given  to  this  condition  is 
tabes  or  locomotor  ataxy.  Since,  broadly  speaking,  hardly  any  two  cases  of  tabes 
are  exactly  alike,  since  the  antitheses  to  the  so-called  classical  signs  may  frequently 
be  met  with,  since  the  origin  is  not  always  the  same,  and,  finally,  since  patients 
have  such  a  wholesome  dread  of  the  condition,  it  appears  to  me  to  be  wiser  to  drojj 
the  terms  tabes  and  locomotor  ataxy,  and  to  supplant  them  by  the  general 
term — degenerative  myelitis. 

Degenerative  myelitis  may  be  of  meningeal  or  ameningeal  origin,  and,  in 
those  cases  in  which  it  is  possible  to  differentiate,  it  should  be  done,  because 
the  prognosis  is  better,  and  treatment  ma}^  be  expected  to  be  more  efficacious,  in  the 
meningeal  than  in  the  ameningeal  form. 

It  may  be  impossible  to  differentiate  the  two  types,  and  often  one  has  to  watch 
the  effects  of  treatment,  before  being  able  to  do  so.  A  close  attention  to  the  follo-R-ing 
points  will  assist  the  observer  to  know  with  which  type  he  is  dealing. 

The  onset  of  symptoms  is  slower,  and  the  progress  of  the  disease  is  much  more 
insidious  in  the  meningeal  form.  As  a  rule,  the  meningeal  form  begins  sooner  after 
the  infection  than  does  the  ameningeal  form.  The  patient  loses  weight  more  quickly, 
and  appears  to  be  more  generallj'  affected,  in  the  ameningeal  form.  Trae  Argyll- 
Robertson  pupils,  i.e.,  pupils  which  are  of  the  same  size,  and  react  to  accom- 
modation and  not  to  light,  are  a  more  common  symptom  in  the  meningeal  form. 


THE   CLINICAL   ASPECT   OF    SYPHILIS   OF   THE    NERVOUS   SYSTEM.  245 

In  the  other  form,  the  pupils  are  often  irregular,  and  the  reflexes  may  be  only 
sluggish  to  light  and  sluggish  to  accommodation,  and,  as  a  rule,  the  reflexes  are 
diminished  on  one  side  more  than  on  the  other.  In  the  meningeal  form,  lightning 
pains  are  more  pronounced,  the  knee-jerks  are  always  absent,  and  ataxia  is  generally 
an  early  symptom.  In  the  ameningeal  form  the  pains  may  be  absent,  the  knee-jerks 
may  be  present  and  even  exaggerated,  ataxia  may  not  be  met  with  until  late,  and, 
as  a  rule,  the  altered  cutaneous  and  tendon  sensations  are  more  marked. 

Trophic  disturbances  are  more  frequently  met  with — anyhow  as  earlj^  signs  of 
the  disease — in  the  meningeal  form,  while  paralyses  are  commoner  in  the  ameningeal 
form.  In  the  former,  the  Wassermann  reaction  in  the  blood  is  less  frequently 
positive  than  it  is  in  the  latter.  The  cause  of  this  is  probably  due  to  the  fact  that 
the  ameningeal  form  is  caused  by  a  primary  disease  of  the  blood-vessels  in  the  cord 
itself,  because  the  lesion  is  sometimes  really  only  a  symptom  of  a  general  arterio- 
sclerosis, and  because  aortic  disease  more  frequently  accompanies  this  form,  for,  in 
most  cases  of  syphilitic  aortitis,  the  AVassermann  reaction  of  the  blood  is  positive. 

An  examination  of  the  cerebro-spinal  fluid  helps  one  in  differentiating  the 
two  types  of  myelitis,  but  it  must  be  remembered  that  spontaneous  cure  of  the 
meningeal  form  is  not  a  very  uncommon  sequence  of  events,  hence,  if  such  a  case 
is  met  with,  the  cerebro-spinal  fluid  may  be  normal. 

The  pressure  is  more  often  raised  in  the  meningeal  form,  the  lymphocytosis  is 
more  marked,  and  consists  of  lymphocytes  and  endothelial  cells  onlj*.  The  ratio 
between  the  amount  of  albumin  and  globulin  is  not  so  great,  the  increase  of  globidin 
is  not  so  marked,  and  the  Wassermann  reaction,  when  tested  quantitatively,  is  not 
so  positive.  In  both  conditions  there  is  an  increase  of  globulin,  but  there  is  a  greater 
increase  of  albumin  and  a  lesser  increase  of  globulin  in  the  meningeal,  than  in  the 
ameningeal  type,  therefore  the  difference  between  the  two  is  less  marked  in  the  former. 

When  attempting  to  differentiate  the  two  forms,  every  pomt  must  be  taken 
into  account,  and  the  diagnosis  must  not  rest  on  one  or  two  only,  since  the  stage 
of  the  disease,  its  severity  and  localisation — i.e.,  as  to  whether  the  process  is  mainly 
cervical  or  mainly  lumbar — are  strong  influencing  factors. 

I  do  not  want  to  mention  all  the  symptoms  of  degenerative  myelitis,  as  they 
are  legion,  and  can  be  better  studied  elsewhere  ;  but  I  will  mention  those  which 
the  reader  is  most  likely  to  come  across,  and  for  which  there  is  a  probable 
explanation.  Mention  will  be  made  of  the  Argyll-Robertson  pupil  first,  because 
the  opinions  as  to  its  origin  are  much  at  variance.  The  most  probable  explanation 
of  this  phenomenon,  to  my  mind,  is  that  it  is  due  to  an  affection  of  the  cervical 
sympathetic.  The  pupillo-dilator  fibres  arise  from  the  first,  second,  and  third  dorsal 
nerves.     They  pass  upwards,  in  the  ascending   branch   of  the  superior  cervical 


246  THE   BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

ganglion,  and  thence  to  the  Gasserian  ganghoii,  reaching  the  eyeball  through  the 
first  division  of  the  fifth  and  the  long  ciliary  nerves. 

The  proof  of  this  is  forthcoming,  in  the  fact  that  the  fibres  which  travel  along 
the  first  division  of  the  fifth  travel  along  the  nasal  nerve.  Now,  as  many  observers 
are  aware,  the  tactile  sensation  in  the  skin  over  the  nose  is,  in  a  very  large  percentage 
of  eases,  very  considerably  lessened.  Again,  this  pupil  phenomenon  is  more 
constant  in  the  meningeal  form  of  degenerative  myelitis — in  fact,  sympathetic 
nerve  lesions  are  in  general  more  common  in  this  form,  probably  owing  to  the 
implication  of  the  nerve  roots  being  easier  in  a  primarily  meningeal  infection. 

It  is  possible  that  a  lesion  of  the  sympathetic  nervous  system  is  primarily 
responsible  for  laryngeal  and  gastric  crises,  and  also  for  those  unpleasant  cases  in 
which  the  pulse  slows  down  and  finally  stops  for  a  brief  interval  of  time,  and  the 
patient  becomes  almost  unconscious,  and  turns  a  very  bad  colour.  I  had  one  case 
in  which  these  cardiac  symptoms  were  most  distressing,  and  no  anti-specific  treat- 
ment could  be  administered,  as  it  always  aggravated  the  attacks.  This  same 
patient  had  very  severe  gastric  crises. 

Concerning  the  other  symptoms  to  be  mentioned,  it  must  be  borne  in  mind 
that  almost  any  one  may  occur  alone,  often  for  some  years,  that  almost  any  one 
may  precede  or  succeed  the  other  symptoms,  and  that  almost  any  one  may  persist, 
in  spite  of  the  fact  that  spontaneous  cure  has  resulted. 

One  of  the  most  common  symptonas  of  degenerative  myelitis  is  pain.  The 
pains  may  be  of  the  nature  of  crises,  or  lightning  pains  down  the  extremities,  usually 
down  the  legs.  The  abdominal  pains  are  very  apt  to  be  mistaken  for  biliary  or 
renal  colic,  or  some  intestinal  trouble.  I  have  had  three  patients  who  had  had 
gastro-jejiinostomy  performed,  and  one  of  the  patients  had  been  operated  upon 
twice ;  therefore,  in  all  acute  abdominal  conditions,  the  surgeon  should  exclude 
degenerative  myeUtis  before  undertaking  an  operation. 

The  lightning  pains  in  the  extremities  are  apt  to  be  mistaken  for  rheumatism 
or  neuritis,  but  the  following  are  points,  the  remembrance  of  which  should  minimise 
the  observer's  risk  of  making  an  error : —  ' 

If  the  lightning  pains  are  in  the  arm,  they  are  usually  limited  to  the  region  of 
the  ulnar  distribution ;  and  the  skin  over  this  area,  even  if  there  are  no  pains,  is 
very  often  insensitive. 

If  the  lightning  pains  are  in  the  lower  limbs,  they  are  usually  most  marked 
below  the  knee.  They  are  often  limited  to  the  heels,  ankles,  or  toes,  and  are  very 
liable  to  affect  one  spot  at  one  time,  and  another  spot  at  another. 

Reduced  tactile  sensation  is  very  marked  in  the  skin  of  the  feet  and  ankles, 
but  it  tends  to  become  normal  again  as  the  knees  are  reached. 


THE    CLINICAL    ASPECT   OF   SYPHILIS   OF  THE   NERVOUS   SYSTEM  247 

Pains  are  due  to  the  degeneration  of  those  fibres  which  connect  the  posterior 
nerves  with  the  cord.  As  I  have  already  stated,  when  dealing  with  peripheral 
neuritis,  provided  the  degeneration  of  sensory  nerves  has  progressed  to  a  certain 
extent,  pains  will  persist,  in  spite  of  the  fact  that  the  cause  of  the  degeneration 
has  vanished. 

Analgesia  is  by  no  means  limited  to  the  areas  above  mentioned.  The  loss  of 
sensibility  to  pain,  in  the  skin  of  the  nose,  is  a  very  common  symptom,  and  the 
analgesia  of  the  skin  of  the  chest,  the  upper  margin  of  the  zone  lying  at  the  level 
of  the  second  rib  in  front,  is  practically  speaking  a  constant  sign. 

Although  the  loss  of  the  knee-jerk  is  a  very  common  symptom,  it  must  not 
be  forgotten  that,  in  some  cases,  they  are  not  only  present,  but  they  may  be  even 
exaggerated. 

The  loss  of  the  knee-jerk  depends  on  degeneration  of  those  fibres,  or  their 
collaterals,  which  pass  to  the  motor  cells  in  the  ventral  horns  of  the  spinal  cord, 
hence  it  will  be  understood  why  the  loss  of  the  knee-jerk  is  more  common  in  the 
meningeal  than  in  the  ameningeal  form  of  degenerative  myelitis.  The  explanation 
of  the  converse  is  equally  clear.  If  the  lesion  commences  in  the  anterior  part  of 
the  cord,  the  knee-jerks  will  be  exaggerated,  and  only  when  the  posterior  columns 
are  reached  will  the  reflexes  vanish. 

Rhomberg's  sign  is  due  to  the  degeneration  of  certain  fibres  in  the  posterior  and 
lateral  columns,  and  therefore  again  is  most  marked  in  the  meningeal  form — 
indeed,  in  some  cases  of  ameningeal  degenerative  myelitis,  not  only  is  Rhomberg's 
sign  absent,  but  the  patient  is  not  ataxic.  The  ataxic  gait  is  supposed  to  be  due  to 
a  certain  set  of  nerve  fibres  which  terminate  in  Clarke's  column,  which  is  indirectly 
connected  with  the  cerebellum,  and  part  of  the  brain,  which  is  well  known  to  exercise 
a  constant  controlhng  and  co-ordinating  influence  on  volitional  movements,  and 
especially  on  those  which  maintain  equilibrium. 

Another  very  common  symptom  of  degenerative  myelitis  is  a  diminution  or 
complete  loss  of  all  sexual  desire. 

Other  less  constant  symptoms  are  insensibility  of  the  tendons,  Charcot's  joint, 
perforating  ulcers,  whitlows,  and  spontaneous  fracture  of  the  patella  or  os  calcis, 
■  and  bladder  disturbances.  Of  these,  the  first  is  not  infrequently  a  very  striking 
sign,  and  it  is  an  easy  one  to  elicit.  The  tendo  Achillis,  when  pressed  hard,  is  pain- 
less. The  same  phenomenon  may  be  experienced  ■with  the  biceps  tendon  at  the 
bend  of  the  elbow  ;  but,  as  in  most  cases  of  degenerative  myelitis,  the  signs  and 
symptoms  of  the  upper  extremities  are  not  so  pronounced  as  those  of  the  lower, 
for  the  simple  reason  that  the  lesion  is  usually  below  the  cervical  enlargement  of  the 
cord.    Insensibility  of  the  tendo  Achillis  generally  goes  by  the  name  of  Abadie's  sign. 


CHAPTER  XXV. 
SYPHILIS  IN   WOMEN. 

Syphilis  in  women  may  be  looked  upon  as  the  greatest  curse  of  the  disease, 
since  a  woman  who  has  once  conceived  a  syphilitic  infant  may  infect,  in  utero,  all 
her  subsequent  offspring,  although  the  father  of  the  latter  may  be  a  different  husband 
who  has  never  suffered  from  the  disease. 

To  make  matters  worse,  conceptional  syphilis  is  not  recognised  until  the  infant 
has  been  seen  to  settle  the  diagnosis,  owing  to  the  fact  that  many  mothers  show  no 
evidence  of  the  disease  until  after  the  child-bearing  period  is  over,  as  the  following 
two  cases  illustrate  : — • 

Case  42. — Mrs.  A.  B.,  aged  46  j^ears,  came  up  to  hospital  in  March,  1910, 
complaining  of  a  rash  on  her  right  arm.  The  rash  had  appeared  about  Christmas, 
1909,  and,  some  short  time  before,  she  had  had  some  sore  places  on  the  right 
leg.  The  lesion  on  the  arm  was  a  gumma,  and  the  right  leg  was  covered  with 
the  scars  of  gummatous  ulceration.  This  patient  was  21  years  old  when  she 
married,  and  neither  before  her  marriage  nor  since,  until  the  date  above-mentioned, 
had  she  ever  experienced  the  slightest  evidence  of  syphilis.  She  had  had  four 
miscarriages ;  eleven  children  were  born,  two  of  whom  were  still  living — the 
results  of  the  second  and  fourth  pregnancies.  All  the  other  children  had  died 
within  six  months  after  birth,  as  the  result  of  syphilis.  Her  last  pregnancy 
had  been  a  miscarriage,  immediately  after  which  she  developed  a  bad  leg ; 
this  period  also  corresponded  with  the  change  of  life.  The  patient  had  giVen  a 
strong  positive  Wassermann  reaction.  Her  second  pregnancy  resulted  in  the 
birth  of  a  son,  who  had  given  a  negative  Wassermann  reaction,  as  had  also  his 
wife  and  child.  The  fourth  pregnancy  resulted  in  the  birth  of  a  daughter,  who  had 
also  given  a  negative  Wassermann  reaction.  Neither  child  had  shown  the  least 
taint  of  the  disease. 

Case  43. — L.  B.,  aged  47  years,  had  come  up  to  hospital  complaining  of  sores,  on 
the  calf  of  the  right  leg,  which  were  typical  gummata.  As  in  the  preceding  case, 
the  ulcers  had  appeared  just  after  the  "  change  of  life."     The  patient  had  been 


SYPHIIJS    IX   WOMEN.  249 

pregnant  nine  times :  the  eliildren  had  mostly  been  premature.  Some  liad 
been  born  alive,  others  born  dead,  but  not  one  had  lived  for  more  than  three 
weeks. 

Since  1910  I  have  seen  numerous  similar  cases,  in  all  of  whom  I  was  able  to 
obtain  a  positive  Wassermann  reaction,  provided  the  child-bearing  period  was 
over.  This  led  me  to  rely  upon,  and  to  do  the  test,  in  every  case  in  which  a  syphilitic 
infant  had  been  born,  when,  to  my  surprise,  I  found  that  many  cases  of  women 
who  were  giving  birth  to  syphilitic  children  themselves  gave  a  negative  Wasser- 
mann reaction. 

A  rough  rule  can  be  formulated,  viz.,  that  if  a  woman  contracts  syphilis  after 
she  has  conceived,  the  Wassermann  reaction  will  be  positive,  because  the  disease 
becomes  generalised,  and  behaves  in  the  ordinary  way  ;  that  if  a  woman  contracts 
syphilis  at  the  time  of  conception,  the  Wassermann  reaction  may  be  negative, 
because  the  disease,  even  if  it  do  become  generalised  then,  does  not  give  rise  to 
symptoms  until  some  later  date. 

Herein  we  have  the  explanation  why  such  patients  only  develop  manifestations 
after  the  child-bearing  period  is  over,  and  why  it  so  frequently  happens  that 
the  first  and  last  pregnancies  result  disastrously,  while  one  or  more  healthy 
children  may  be  born  in  the  middle.  It  is  interesting  to  inquire  into  the  rationale 
of  conceptional  syphilis. 

The  germ  must,  in  the  first  instance,  be  conveyed  by  the  semen.  But  does  the 
germ,  which  travels  with  the  embryo  along  the  Fallopian  tube  into  the  uterus, 
develop  after  a  time  into  the  gamete  forms  described  by  me,  which  I  regard  as 
responsible  for  the  s}-mptoms,  at  the  expense  of  the  embryo — with,  maybe,  its 
death — leave  some  of  the  sporozoites  behind  after  its  expulsion,  to  be  already  there 
to  develop  at  the  expense  of  the  next  embryo  ?  Or,  does  the  mother  become  infected 
directly,  but  the  symptoms  are  prevented  from  recurring,  owing  to  the  formation 
of  some  chemical  substance,  possibly  in  the  form  of  a  lipoid-globulin  compound 
from  the  embryo,  which  prevents  the  gametes  from  being  developed  ? 

When  the  question  was  discussed  after  the  Spirochaeta  pallida  had  been 
discovered,  when  the  Spirochaeta  pallida  was  held  to  be  responsible  for  everj'thing 
syphilitic,  only  confusion  resulted.  If  my  discovery  of  the  Leucocytozoon  syphilidis 
be  accepted,  and  the  views  accepted  that  the  sporozoite  is  the  infective  agent,  and 
that  the  gametes  are  responsible  for  the  symptoms,  the  alternative  need  not  appear 
in  the  above  illustration,  as  both  in  part  may  turn  out  to  be  correct. 

It  may  be  considered  that  the  sporozoites,  themselves  onlv  potentially  harmful, 
travel  in  the  semen,  reach  the  uterus  with  the  embryo  along  the  Fallopian  tube, 
and  find  themselves  in  both  the  maternal  and  foetal  portions  of  the  embryo.     Those 


250  THE   BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

in  the  foetal  portion,  after  a  period  of  some  weeks,  develop  into  gametes,  which  may 
or  may  not  kill  the  embryo. 

Those  in  the  maternal  portion  find  themselves  unable  to  develop,  owing  to  a 
chemical  substance,  from  the  chorionic  cells,  which  circulates  in  the  mother's  blood 
but  not  in  the  foetal,  and  so  they  remain  dormant  for  a  tune.  Herein  lies  the 
solution  of  the  phenomenon  that  a  mother  may  give  birth  to  a  severe  syphilitic 
infant,  without  herself  even  giving  so  much  as  a  positive  Wassermann  reaction. 

The  theory  above  put  forward  will  also  explain  why  a  woman  who  has  once 
given  birth  to  a  syphilitic  child  is  always  liable  to  do  so  again,  although  the  father 
of  her  later  children  may  be  another  husband,  who  has  himself  never  suffered 
from  the  disease. 

Hence  the  necessity  for  treating  such  a  case  throughout  the  whole  period  of 
each  succeeding  pregnancy. 

There  is  no  necessity  to  refer  to  the  lengthy  discussion  relating  to  the  greater 
frequency  of  maternal  over  paternal  infection,  or  vice  versa.  A  father  may  be  the 
cause  of  his  first  infant  contracting  the  disease  ;  the  mother,  ipso  facto,  becomes 
likewise  affected ;  her  future  children  may  be  by  another  and  a  healthy  man,  but 
they  may  all  be  syphilitics.  Therefore,  maternal  syphilis  must  obviously  be  more 
important  and  more  frequent  than  paternal  sj^philis. 

The  only  reliable  information  as  to  the  national  loss  by  ante-natal  syphilis  is 
the  oft-culled  figures  of  Hochsinger.^  ^ 

This  observer,  since  1869,  had  been  able  to  keep  under  observation  134  women 
who  showed  no  signs  of  syphilis,  but  had  given  birth  to  syphilitic  children.  These 
women  had  given  birth  569  times,  253  of  the  children  being  born  dead,  i.e.,  44*4  per 
cent. ;  and  316  were  born  alive.  Of  those  born  alive  263  were  syphilitic,  and  53 
were  without  a  taint.  Of  the  263,  55  died  before  the  fourth  year,  i.e.,  over  20  per 
cent. 

These  figures  are  so  appalling,  that  it  is  of  the  utmost  importance  for  every 
medical  man  to  have  particular  regard  for  the  welfare  of  syphilitic  women,  in  seeing 
that  they  are  properly  treated.  ' 

Keference  must  now  be  made  to  what  we  have  called  Colles'  law,  although 
Colles  originally  stated  merely  that  syphilitic  children  did  not  infect  their 
mothers.  Colles  neither  enlarged  upon  this  nor  attempted  to  give  a  reason  for  the 
phenomenon. 

It  is  perfectly  true  that  syphilitic  children  cannot  infect  their  mothers,  the 
reason  being  that  the  mothers  are  invariably  syphilitic  themselves,  in  spite  of  the 
fact  that  they  may  never  have  had  symptoms  nor  have  given  even  a  positive 
Wassermann    reaction.     Colles'  observation  goes  strongly  to  support    my    view 


SYPHILIS   IN   WOMEN.  251 

of  there  being  jjhases  in  the  life  history  of  the  organism  of  syphilis  other  than  the 
Spirochaeta  pallida. 

The  observation,  moreover,  shows  that  no  deductions  can  be  made  from  a 
negative  Wassermann  reaction,  where  women  are  concerned. 

Profeta's  law  states  that  a  healthy  child  boru  of  a  syphilitic  mother  is  immune 
against  syphilis,  but  loses  its  immunity  at  puberty.  Apparently  healthy  children 
may  be  born  of  syphilitic  mothers  but  yet  be  syphilitic,  although  they  may  never 
show  signs  or  symptoms  of  the  disease. 

On  the  other  hand,  absolutely  healthy  children  may  be  born  of  syphilitic 
mothers,  but  they  are  not  immune  against  the  disease.  This  possibility  should 
especially  be  borne  in  mind  to-day,  when  it  is  almost  always  possible — by  thoroughly 
treating  a  syphilitic  mother  throughout  the  whole  of  her  pregnancy — to  render 
the  child  non-syphilitic  at  birth.  Under  such  conditions,  the  mother  should  never 
be  allowed  to  suckle  the  child,  because  in  some  cases  the  mother  is  not  cured  by 
the  treatment,  and  the  infective  agent  can  pass  through  in  the  milk. 

While  CoUes'  law  still  holds  good,  Profeta's  law  does  not. 

The  Primary  Sore. 

Many  of  the  points  about  to  be  mentioned  have  already  appeared  in 
Chapter  XIV.,  but  as  the  clinical  diagnosis  of  the  initial  lesion  is  the  most  important 
part  of  the  struggle  against  the  whole  disease,  recapitulation  is  pardonable. 

A  chancre  may  occur  in  any  part  of  the  \'ulva,  vagina  or  cervix  uteri.  It 
always  begins  as  a  tiny  papule,  which  in  time  becomes  eroded  on  the  surface. 

No  value  should  be  attached  to  history.  Asking  a  patient  how  soon  after 
connection  a  sore  appeared  is  often  useless,  because  not  infrequently  a  woman 
does  not  know  that  she  has  even  got  a  sore.  The  good  old  rule  that  multiple  sores 
are  soft  sores,  single  ones  syphilitic,  has  led  many  astray.  A  single  sore  on  the 
genitals  is  usually  syphilitic,  but  not  invariably.  Induration,  when  present,  is 
positive,  but  its  absence  does  not  negative  syphilis.  Many  of  the  multiple  primary 
sores  on  the  external  genitals  of  women  never  are  indurated.  Of  the  greatest  value 
in  differential  diagnosis  is  the  appearance. 

A  syphilitic  sore  is  sharply  circumscribed,  not  irregular  or  undermined  at  the 
edge.  The  erosion  is  either  on  a  level  with  the  surrounding  skin  or  raised  above 
it.  The  surface  is  often  dry,  especially  when  on  the  labium  majus ;  it  has  a  shiny 
appearance,  bleeds  easily  on  friction,  and  does  not  discharge  freely. 

There  is  none  of  that  surrounding  inflammation  which  is  so  typical  of  soft  sores 
and  of  other   infective  sores,  because  the  organisms  of  the  latter  are  pus-producing 


252  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT    OF    SYPHILIS. 

organisms,  while  the  Leucocytozoon  syphilidis  is  not.  This  is  also  the  reason  why 
the  inflammatory  sores  are  undermined,  ragged-edged,  and  depressed  in  the  centre 
beneath  the  circumference — ulcers,  in  contradistinction  to  erosions — and  an  ulcer 
covered  with  pus,  which  discharges  freely. 

Clinical  Types  op  Chancres. 

1.  Erosive  chancre. — This  is  the  most  typical  of  all  chancres.  It  is  found  most 
commonly  on  the  labia.  There  is  often  a  corresponding  sore  on  the  opposite  side. 
It  varies  in  size  from  that  of  a  threepenny  to  that  of  a  shilling  piece,  or  it  may  be 
bigger.  It  is  red,  has  a  shiny  surface,  the  erosion  is  flush  with  the  surface,  and  the 
circumference  is  sharply  circumscribed  and  regular.  Induration  is  usually  present, 
but  a  common  symptom  is  the  non-inflammatory  hard  oedema  of  the  labium  on 
which  the  sore  is  situated.     The  oedema  is  due  to  syphilitic  lymphangitis. 

2.  Papido-piistular  chancre. — This  chancre  is  almost  invariably  single,  and 
practically  only  found  on  the  true  skin. 

•3.  Ecthymatoiis  chancre. — This  chancre  is  also  most  frequently  found  on  the 
skin.  It  is  usually  single,  sharply  circumscribed,  raised  and  crusted  on  the  surface. 
With  this  chancre  there  is  often  some  inflammation  of  the  surrounding  tissues, 
owing  to  the  fact  that  it  is  a  chancre  which  has  become  secondarily  infected. 

4.  Ulcerative  chancre. — This  may  be  a  sequela  of  any  chancre  which  becomes 
secondarily  infected.     A  phagedaenic  chancre  is  a  further  stage  of  this  variety. 

5.  Pseudo-membranous  chancre. — These  chancres  are  usuall)'^  multiple,  they 
are  about  the  size  of  a  threepenny  piece,  they  have  a  yellow  base,  which  may 
be  flush  with  the  surface  or  raised  above  it,  and  there  may  be  a  red  inflammatory 
ring  surrounding  each  lesion.     These  chancres  are  usually  slightly  indurated. 

At  first  sight,  the  chancres  look  like  soft  sores,  but  they  can  be  easily  distin- 
guished . 

Although  the  former  have  a  yellow  base,  no  pus  comes  away  from  them.  They 
are  regular  in  outline,  unlike  soft  sores.  And,  again,  soft  sores  always  tend  to 
advance  in  one  direction,  while  healing  is  taking  place  at  the  opposite  pole.  Further- 
more, the  surrounding  inflammatory  zone  is  much  more  apparent  in  the  soft  sore 
lesions. 

6.  Hypertrophic  chancre. — This  type  of  chancre  is  uncommon,  but  may  some- 
times be  met  with  on  the  labia  majora.  It  is,  almost  invariably,  single,  and  it  closely 
resembles  the  hypertrophic  large  spore  ringworm  seen  on  the  hairy  parts  of  the 
face. 

7.  Lenticular  chancre. — These  chancres  are  invariably  multiple.     They  vary  in 


SYPHILIS    IN   WOMEN.  253 

diameter  from  1-5  millimetres;  they  are  circular,  regular  in  outline,  and  are  merely 
abrasions. 

8.  The  furrowed  chancre. — This  chancre  may  be  single  or  multiple.  It  is  never 
indurated,  and  at  first  sight  looks  not  unlike  a  soft  sore.  It  is  sharply  circumscribed 
and  circular.  There  is  no  surrounding  inflammation  ;  there  is  little  loss  of  surface, 
but  the  base  of  the  chancre  is  yellow  and  very  uneven,  not  unlike  a  ploughed  field. 

There  are  several  other  types  of  chancre  which  are  merely  transitions  of  the 
above,  and  naturally  the  characters  of  a  chancre  may  alter,  according  to  the  position 
in  which  it  is  situated.  For  instance,  an  erosive  chancre  occurring  on  either  side 
of  a  fold  may  be  deeply  fissured  in  the  centre.  Then  the  mixed  chancre  has  to  be 
considered,  i.e.,  when  a  patient  is  infected  at  the  same  time  with  the  bacillus  of  soft 
sore  and  with  the  organism  of  syphilis.  Owing  to  the  short  incubation  period  of 
the  former,  and  the  long  incubation  period  of  the  latter,  a  soft  sore  may  appear 
long  before  the  papule  of  the  syphilitic  erosion  has  begun  to  develop.  In  the  case 
of  a  mixed  infection,  the  soft  sore  may  not  heal,  and  so  it  may  gradually  develop 
into  a  chancre,  so  that,  in  every  case  of  a  soft  sore  infection,  the  patient  should  be 
kept  under  observation  for  two  months  at  least. 

Most  of  the  types  of  chancres  above  described  may  occur  in  the  vagina,  and 
on  the  cervix  uteri.  In  the  vagina,  they  seldom  give  rise  to  difficulties  in  diagnosis, 
because  other  venereal  infections  very  rarely  attack  that  tract.  Chancres  on  the 
cervix  are  frequently  diagnosed  wrongly,  and  then  are  usually  mistaken  for  erosions, 
aphthous  ulcers,  gummata  and  tuberculous  ulcers,  and  Vlcera  mollia. 

Cervical  Chancre. 

Chancres  of  the  cervix  nearly  always  give  rise  to  an  indurative  oedema  of  the 
whole  cervix,  often  giving  it  a  characteristic  dark  red-purple  colour,  as  if  it  were 
venously  congested. 

Erosions  can  be  distinguished  from  chancres,  because  the  cervix  is  soft,  and  of 
normal  colour ;  the  erosion  is  bright  red,  not  as  a  rule  sharply  circumscribed.  In 
some  areas,  it  is  difficult  to  say  where  erosion  ends  and  normal  nmcous  membrane 
begins,  a  feature  which  is  common  to  traumatic  lesions.  If  an  erosion  is  covered 
with  pus  which  looks  like  a  membrane,  it  is  easily  rubbed  off,  and  this  is  not  the 
case  with  a  primary  sore. 

The  follicular  and  papillary  erosions  are  too  distinctive  to  be  confused  with  any 
other  condition. 

In  a  majority  of  cases  where  there  is  an  erosion,  there  is  a  discharge  or  exuda- 
tion from  the  cervical  canal,  and  this  discharge  was  possibly  primarily  responsible 
for  the  erosion. 


254  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT    OF    SYPHILIS. 

ApJithous  ulcers  are  soft,  multiple,  either  flush  with  the  surface  or  only  a  little 
depressed  beneath  it.  They  have  no  undermined  edges,  such  as  soft  sores  frequently 
have.  They  have  a  membranous  base  which  cannot  be  rubbed  away,  and  they  are 
almost  invariably  surrounded  by  a  narrow  inflammatory  ring. 

Gummata  are  more  deeply  ulcerated  than  chancres.  Unlike  chancres,  they 
tend  to  spread  a  little,  and,  for  the  degree  of  ulceration,  the  surrounding  parts  are 
softer  and  less  inflammatory  than  would  be  the  case  if  in  an  ulcerative  chancre. 

Tuberculous  ulcers  only  occur  in  women  who  have  marked  signs  of  tuberculosis 
elsewhere.  The  ulcers  are,  as  a  rule,  circumscribed,  and  can  generally  be  diagnosed 
from  other  forms  of  ulceration,  because,  surrounding  the  ulcers,  tubercles  are  fre- 
quently to  be  seen,  and  tuberculous  ulcers  are  very  painful. 

Ulcera  mollia. — The  sores  are  soft,  multiple,  undermined,  and  surrouiided  by  a 
red  and  inflammatory  ring.  They  discharge  freel)',  and  the  ulcers  quickly  spread, 
but  as  a  rule  in  one  direction  only. 

Syphilitic  sores  of  the  external  genitalia  are  frequently  mistaken  for  soft  sores. 
This  need  not  be  so,  for  they  can  be  readily  distinguished  clinically.  Failing 
clinical  differentiation,  they  may  be  distinguished  pathologically, since  the  spirochaeta 
can  be  found  in  the  former,  and  Ducrey's  streptobacillus,  a  gram  negative  organism, 
in  the  latter.  Syphilitic  sores  may  be  confounded  with  Vulvitis  erosiva  et 
gangrenosa,  and  with  the  Ulcera  pseudo-venerea.  A  soft  sore  possesses  a  feature 
which  is  possessed  by  practically  no  other  ulcer  with  which  we  are  concerned  ; 
it  is  auto-inoculable. 

The  Ulcera  pseudo-venerea  have  only  very  recently  been  recognised,  owing  to 
the  work  of  Lipschiitz.^  Their  occurrence  should  always  be  borne  in  mind,  since 
virgins  are  most  frequently  aSected,  therefore  they  are  not  venereal  in  origin,  in 
the  sense  that  sjrphilis  is  so. 

They  may  occur  "  over  night,"  and  are  usually  ushered  in  with  fever,  rigors  and 
local  pains.  With  or  without  treatment  they  tend  to  disappear  quickly.  In  other 
cases  the  onset  is  not  so  sudden,  and  the  course  of  the  trouble  may  last  several 
weeks.  ' 

The  ulcers  are  soft,  deep,  usually  undermined,  and  the  base  is  covered  with 
pus.  Owing  to  the  close  resemblance  these  ulcers  bear  to  soft  sores,  a  bacteriological 
examination  is  usually  necessary.  The  organism  always  found  in  Ulcera  pseudo- 
venerea  is  a  Gram  positive  bacillus,  occurring  either  alone  or  in  chains,  or  in  threads 
like  a  streptothrix.  Its  ends  are  square,  and  no  success  has  so  far  been  achieved 
in  attempts  to  cultivate  it. 

Oddly  enough,  two  cases  of  which  I  have  notes  gave  a  positive  Widal's  reaction. 
Lipschiitz  also  had  a  similar  experience,  although  none  of  the  cases  developed  other 


SYPHILIS   IN   WOMEN.  255 

symptoms  of  typhoid.  A  bacteriological  examination  will  also  serve  to  distinguish 
these  ulcers  from  the  Ulcera  gmigrenosa,  in  which  the  fusiform  bacilli  and  un- 
evenly coiled  spirochaetae  are  found  living  in  symbiosis — the  same  organisms  which 
cause  Vincent's  angina. 

Generalised  Syphilis. 

The  marked  difference  between  the  stage  of  generalisation,  as  it  affects  men 
and  women,  is  the  very  much  larger  proportion  of  the  latter  which  develops  Leuco- 
derma  colli.  The  areas  of  leucoderma  may  be  discrete  or  confluent.  When 
confluent,  they  are  frequently  arranged  in  the  form  of  a  rosette.  These  areas  occur 
where  macules  have  been,  and,  not  infrequently,  in  the  centre  of  the  depigmented 
area,  a  hyperpigmented  spot  is  to  be  seen,  and  it  occurs  where  a  papule  has  succeeded 
the  macule. 

The  condition  is  more  common  in  brunettes  than  in  blondes,  because  it  is  more 
easily  seen.  The  condition  is  probably  more  common  in  women  than  in  men,  owing 
to  the  skin  being  more  delicate  and  not  so  red  in  the  former,  therefore  the  contrast 
is  more  noticeable.  Most  women  exhibit  the  condition  ;  it  may  be  limited  to  the 
neck  and  anterior  folds  of  the  axillae,  or  it  may  occur  over  the  whole  body. 
Treatment  does  not  alter  the  condition  ;  it  is  a  chronic  one,  begins  in  the  early 
stage  of  the  generalisation  of  the  virus,  and  only  tends  to  disappear  in  course  of 
time,  which  is  often  a  matter  of  years,  usually  from  one  to  four  years. 

Syphilis  of  the  Generative  Organs. 

Unfortunatel)'^,  this  branch  of  syphilis  is  still  more  or  less  veiled  in  obscurity. 
A  few  stray  cases  of  syphilis  of  the  uterus,  Fallopian  tubes,  and  ovaries  have  been 
described,  but  no  light  has  been  thrown  upon  them,  so  far  as  their  differential 
diagnosis  and  pathology  is  concerned. 

Recently,  some  observers  have  attempted  to  gauge  the  relative  frequency  of 
syphilis  as  the  cause  of  chronic  metritis,  by  the  Wassermann  reaction.  In  the 
first  place,  the  percentage  of  positive  results  obtained  was  too  great  to  allow  much 
unportance  to  be  attached  to  them  ;  and,  in  the  second  place,  because  the  reaction 
is  positive,  it  does  not  necessarily  follow  that  the  menorrhagia  and  metrorrhagia 
of  which  the  patient  is  complaining  are  significant  of  a  syphilitic  metritis.  Such 
symptoms  are  common  in  women  who  have  had  children,  but  have  never  suffered 
from  a  venereal  disease. 

They  are  extremely  common  in  women  who  have  had  gonorrhoea,  and  it  is 
absolutely  impossible,   from  either  a   clinical   or  a   pathological  examination,  to 

R 


256  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF    SYPHILIS. 

diagnose  a  gonococcal  from  a  syphilitic  metritis.  That  sji^hilitic  metritis  cannot 
be  very  common,  is  seen  from  the  fact  that,  if  a  series  of  cases  with  symptoms  of 
chronic  metritis  giving  positive  Wassermann  reactions  be  treated  with  salvarsan 
and  mercury,  in  only  a  small  minority  do  the  symptoms  vanish. 


Wasseemann  Reaction. 

Broadly  speaking,  a  positive  Wassermann  reaction  has  greater  significance, 
and  a  negative  reaction  less  significance,  in  women  than  in  men,  owing  to  the  com- 
plicating factor  of  pregnancy  in  the  former. 

Assuming  that  all  women  are  prospective  mothers,  a  positive  reaction  must 
always  be  interpreted  as  meaning  that  children  born  of  that  parent  are  liable  to  be 
syphilitic.  A  positive  reaction  does  not  necessarily  mean  that  the  woman  has 
active  sj^philis,  but  a  woman  need  not  have  active  syphilis,  to  bear  syphilitic 
children. 

During  the  child-bearing  period,  a  woman  giving  a  positive  AVassermann 
reaction  must,  through  each  and  every  pregnancy,  be  thoroughly  treated,  in  spite  of 
later  changes  in  the  reaction. 

After  the  child-bearing  period  is  over,  a  positive  Wassermann  reaction  can 
mean  no  more  than  that  the  patient  has  had  syphilis,  therefore  there  is  no  indica- 
tion for  treatment,  unless,  upon  a  thorough  examination,  an)'  active  signs  of  the 
disease  are  to  be  found. 

As  a  negative  Wassermann  reaction  may  be  obtained  in  a  woman  who  has 
active  syphilis,  during  the  child-bearing  period,  it  can  be  seen  at  once  that  a  negative 
reaction  is  of  no  value.  Some  of  these  cases  can  be  made  to  give  a  positive  reaction 
after  a  provocative  injection  of  salvarsan,  but  such  a  test  may  fail,  therefore  a 
negative  reaction,  obtained  with  the  blood  withdrawn  48  hours  and  the  fifth  day 
after  the  injection,  means  nothing.  It  is  very  seldom  necessary  to  do  a  Wasser- 
mann reaction  during  the  period  when  a  woman  is  capable  of  bearing  a  child, 
owing  to  the  frequency  of  conceptional  syphilis,  and  to  the  negative  reaction  which 
may  accompany  it. 

Clinical  experience  will  generally  suffice.  If  a  prospective  father  is  known 
to  have  had  syphilis,  he  should,  regardless  of  giving  a  negative  Wassermann 
reaction,  receive  seven  injections  of  neo-salvarsan,  with  five  to  seven  days'  interval 
between  successive  injections.  He  should  also  receive  mercury  for  two  years, 
given  in  the  form  of  eight  weekly  intramuscular  injections  of  grey  oil,  with  two 
months  allowed  to  elapse  between  each  course.  Iodides  should  be  given  for  the 
first  three  weeks  of  each  two  months"  interval. 


SYPHILIS   IN   WOMEN.  257 

Marriage  may  be  allowed  after  the  salvarsan,  but  the  wife  should  not  be  allowed 
to  become  pregnant  until  the  end  of  the  second  year.  If  the  parties  concerned  are 
married,  and  the  husband  develops  s)Tnptoms  of  syphilis,  and  should  his  wife  not 
be  already  syphilitic,  and  should  she  be  desirous  of  having  more  children,  then  the 
husband  should  be  treated  as  in  the  previous  case  and  the  two-year  limit  enforced. 
If  to  a  married  couple  a  syphilitic  child  has  already  been  born,  it  would  be  better 
for  the  father  to  undergo  the  same  treatment  as  above.  It  would  be  essential  for 
the  mother  to  do  so,  and,  moreover,  throughout  each  succeeding  pregnancy  treat- 
ment should  be  prescribed. 

If  the  rule  is  carried  out — to  treat  such  a  woman  during  the  whole  time  she 
■  is  pregnant^ — it  would  not  be  necessary  to  enforce  the  two-year  limit  upon  her. 

The  fact  that  a  child  is  born  healthy,  does  not  prove  that  it  is  not  syphilitic, 
because  symptoms  may  not  develop  for  weeks,  months,  or  even  years.  It  must  also 
be  remembered  that  such  a  child  may  give  a  negative  Wassermann  reaction. 
Even  if  a  syphilitic  child  develops  no  symptoms,  as  a  rule  a  negative  Wassermann 
reaction  obtained  soon  after  birth,  usually  becomes  positive  about  the  sixth  month. 

Owing  to  the  consequences  resulting  from  a  positive  reaction  obtained  in  a 
woman  during  the  child-bearing  period,  the  reader  cannot  be  too  carefully  warned 
against  accepting  any  result,  unless  it  has  been  obtained  by  the  original  method. 
The  modifications  of  the  Wassermann  reaction  are  very  liable  to  give  non-specific 
reactions. 

If  the  original  technique  be  employed, any  result  obtained  with  a  cholesterolised 
antigen  should  be  discarded.  In  my  opinion,  the  only  justifiable  variation  is  to  use 
the  sera  active. 

Difference  Between  Syphilis  in  Men  and  Women. 

It  is  a  well-known  fact  that  syphilis  in  women  is  not  nearly  such  a  serious 
disease — i.e.,  so  far  as  the  individual  herself  is  concerned— as  it  is  in  men.  There 
is  no  difference  in  the  nature  and  severity  of  the  primary  lesions  in  the  two  sexes. 
The  early  manifestations  of  the  generalisation  stage  are  also  much  the  same,  but 
the  later  manifestations  are  very  much  milder  in  women  than  in  men.  Recurrences 
are  fewer  and  milder  in  the  female  sex,  and  arterial  lesions  are,  comparatively 
speaking,  rare.  Gummata,  on  the  other  hand,  may  be  equally  frequent  and  severe 
in  both  sexes. 

There  is  no  doubt  that,  in  women  who  are  bearing  children,  the  symptoms  of 
syphilis  are  even  milder  still.  From  the  facts  just  brought  forward,  one  is  tempted 
to  conclude  that  the  serum  of  women  contains  more  natural  protective  substances 

e2 


258  THE   BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

than  the  serum  of  men  does,  and  that  these  protective  substances  are  still  further 
increased  during  pregnancy.  Owing  to  the  fact  that  the  incidence  of  gummata  in 
both  sexes  is  about  equal,  and  since  gummata  as  a  rule  do  not  break  out  until  after 
the  ages  of  45  to  50  have  been  reached,  it  would  appear  that  women  lose  their 
increase  of  natural  protective  substances  after  the  menopause. 

The  protective  substance  against  syphilis,  as  well  as  against  any  other  infection, 
microbic  or  otherwise  {vide  placenta),  is  the  lipoid-globulin  of  the  serum ;  but,  in 
each  infection,  this  lipoid-globulin  has  a  specific  stereo-chemical  molecular  con- 
figuration, and  there  appears  to  be  no  limit  to  the  range  of  the  specificity. 

The  specificity  does  not  lie  in  the  lipoid-globulin  as  lipoid-globulin,  but  in  the 
foundation  upon  which  the  lipoid-globulin  is  built  up. 

Lipoid-globulin  may  be  likened  to  a  house  which  is  built  of  bricks.  The  house 
is  always  the  same,  but  the  bricks  with  which  it  is  built  vary.  These  bricks  are 
the  amino-acids,  polypeptides,  etc.,  which  go  to  build  up  the  lipoid-globulin,  which 
is  the  house.  Specificity  is  caused  by  the  variation  in  the  bricks.  We  know  that  the 
range  of  specificity  is  unlimited  ;  therefore  the  variation  in  the  bricks  is  not  so 
much  the  alteration  of  one  brick,  as  a  change  in  the  combination  of  several. 

This  being  the  case,  it  is  possible  for  different  infections  to  produce  partly  similar 
combinations  of  the  groups  which  go  to  make  up  the  lipoid-globulin  molecules.  The 
combination  may  be  the  .same  up  to  a  point,  and  then  the  last  brick  or  two  may 
make  all  the  difference. 

If  this  be  the  case,  it  may  so  happen  that  some  of  the  groups  which  go  to  make 
the  syphilitic  lipoid-globulin,  are  also  the  same  as  some  of  those  which  go  to  make 
up  the  lipoid-globulin  of  the  sera  of  women.  In  other  words,  there  is  a  common 
combination  of  the  groups  which  constitute  the  lipoid-globulin  of  syphilitic  sera 
and  the  sera  of  women  up  to  the  menopause,  and  that  the  similarity  becomes  the 
closer  in  women  who  are  pregnant. 

That  this  is  not  pure  theory,  is  proved  by  the  fact  that  the  sera  of  syphilitic 
non-pregnant  women  give  a  positive  Abderhalden's  reaction  with  placental  extract. 

Abderhalden's  reaction  is,  in  my  opinion,  a  physical  reaction  which  depends 
upon  the  adsorption  of  particles  posses.sing  homologous  stereo-chemical  molecular 
configurations.  When  such  an  adsorption  occurs,  the  molecules  are  precipitated, 
and,  when  dialysed,  they  break  up.  The  hydrolysis  results  in  an  increase  of  dialysable 
amino-acids,  which  give  the  positive  ninhydrin  reaction. 

Sera  of  sj^^hilitic  non-pregnant  women  behave,  then,  in  the  same  way  as  the 
sera  of  pregnant  women.  Placental  extract  contains  the  analytic  products  of 
placental  protein  ;  these  products  represent  some  of  the  bricks. 

For  adsorption  to  take  place  between  placental  extract  and  the  sera  of  both 


SYPHILIS   IN   WOMEN.  259 

preguaut  women  and  syphilitic  non-pregnant  women,  the  stereo-chemical  molecular 
configuration  of  the  placental  extract  must  have  its  homologues  in  the  sera. 

This  proves  that  some  of  the  bricks  which  are  responsible  for  the  specificity 
of  the  sera  of  pregnant  women,  towards  placental  extract,  are  likewise  responsible 
for  the  specificity  to  be  met  with  in  a  syphilitic  serum.  Therefore,  the  reason  why 
syphilis  is  a  less  severe  disease  in  women,  is  probably  owing  to  the  fact  that  sexual 
differences  render  the  sera  of  women  more  like  syphilitic  sera. 

1  Hochsinger  (1910),  "  Wien  klin.  Woch.,"  xsiii,  8S1,  9.32. 

^  HoclLsinger  (1898),  ''  Studien  iiber  die  hereditiire  Syphilis."     Leipzig. 

'  Lipschutz  (1913),  '■  Archiv.  f.  Derm.  ii.  Syph.,"  cxiv,  363. 


CHAPTER  XXVI. 
CONGENITAL  SYPHILIS. 

Before  opening  this  chapter,  I  should  like  to  warn  the  reader,  that  when  he 
is  deahng  with  a  case  of  congenital  sj^hihs,  the  possibihty  of  the  infection  being 
acquired  after  birth,  should  always  be  borne  in  niind,  since  a  syphilitic  infection 
of  an  infant  is  an  easy  matter,  and  many  cases  of  acquired  syphilis,  are  labelled 
as  congenital  syphilis.  I  have  in  mind  two  cases  of  supposed  congenital  syphilis, 
which  I  have  recently  seen.  In  the  one,  the  primary  sore  was  on  the  heel ;  and  in 
the  other,  on  the  occiput. 

Syphilitic  infection  causes  abortion,  miscarriage,  or  still-birth  ;  or  the  birth, 
before  or  at  full  time,  of  a  live  child  showing  signs  of  the  disease,  either  at  birth, 
or  at  some  subsequent  period. 

Congenital  syphilis  resembles  the  acquired  form,  the  chief  difference  being, 
that  it  is  a  general  infection  from  the  beginning,  while  the  acquired  variety  com- 
mences with  a  local  lesion  or  chancre.  It  is  a  very  much  more  serious  form  of  the 
disease  than  is  the  acquired  form.  In  the  former,  the  tissues  affected  are  un- 
developed, and  therefore  fall  a  more  easy  prey  to  the  poison,  the  mortality  being 
high,  while  death,  as  the  result  of  acquired  syphihs,  is  the  exception. 

In  the  severer  form,  death  takes  place  in  litem,  and  the  macerated  fcetus  is 
expelled  two  or  three  weeks  later. 

A  history  of  such  an  abortion  occurring  in  each  successive  pregnancy  is 
characteristic  of  syphilis,  but  habitual  abortion  of  a  non-macerated  fcetus,'within 
the  first  four  months  of  pregnancy,  is  not  proof  (or  evidence)  of  syphilis. 

Frequently,  after  a  series  of  abortions,  a  seven  or  eight  months'  child  is  born 
alive.  Premature  labours  likewise  not  uncommonly  run  in  succession,  until, 
finally,  a  full-term,  and  possibly  non-syphilitic,  child  is  born.  It  is  not  at  all 
uncommon  to  find  the  first  few  and  the  last  few  pregnancies  disastrous,  one  or  two 
healthy  children  being  born  in  between. 

Many  syj)hilitic  children,  though  born  alive,  die  a  few  hours  or  a  few  days  after 
birth,  section  usually  showing  marked  syphilitic  changes  in  the  internal  organs. 


CONGENITAL   SYPHILIS.  261 

Such  children  come  into  the  world  thin  and  niarasmic,  with  dry,  kx  and  wrinkled 
skin,  an  old  and  haggard  facial  expression,  and  a  weak  and  scarcely  audible  voice. 
Arrest  of  development  may  occur  at  any  period  of  extra-uterine  life  ;  growth  is 
stunted  ;  there  is  lateness  in  dentition,  speech,  and  walking  ;  frequently  there  is 
deficiency  of  intelligence,  and  also  a  delay  in  the  changes  of  puberty. 

The  degrees  to  which  errors  of  development,  such  as  hare-lip,  cleft-palate,  club- 
foot, Spina  bifida,  and  hydrocephalus,  are  dependent  upon  syphilis,  must  at  present 
remain  unsettled,  but,  in  a  certain  proportion  of  cases,  a  definite  relationship  seems 
to  be  suggested. 

The  danger  of  producing  a  syphilitic  child  is  greatest  during  the  first  year 
after  the  contraction  of  the  disease  ;  is  great  during  the  first  four  years,  but  is 
largely  influenced  by  treatment ;   it  then  diminishes. 

If  the  parents  are  properly  treated,  healthy  children  can  be  produced. 

Although  of  extremely  rare  occurrence,  cases  have  been  recorded  in  which 
the  disease  was  handed  down  to  the  third  generation,  i.e.,  cases  of  congenital 
syphilitics  propagating  syphilis.  I  have  so  far  only  come  across  two  instances, 
one  of  which  is  worth  recording. 

Case  44. — A  woman,  aged  37,  brought  to  see  me  two  of  her  children,  sufl'ering 
from  ringworm.  The  mother  had  signs  of  old  bilateral  interstitial  keratitis,  fissures 
at  the  angles  of  the  mouth,  and  well-marked  Hutchinson's  teeth.  She  had  had 
seven  children,  no  abortions  or  miscarriages.  I  examined  the  seven  children,  and 
found  that  two  o]iIy  had  any  symptoms  of  syphilis,  the  others  were  perfectly 
healthy.  These  two  died  later,  at  the  ages  of  8  and  9,  of  degenerative  encephalitis, 
while  the  other  children  remain  perfectly  healthy,  but  they  are  said  to  be  extremely 
backward  at  school.  The  mother's  Wassermann  reaction  was  positive,  the  father's 
was  negative ;  the  two  affected  children  gave  a  positive  reaction,  two  of  the  others 
gave  a  doubtful  reaction,  which  two  years  later  had  become  negative,  and  the 
other  three  gave  a  negative  reaction  throughout. 

Symptoms. 

A  child  may  have  manifestations  of  syphilis  in  utero,  and  they  may  jjass  off  before 
birth,  for  children  have  been  born  with  synechiae,  the  sequelae  of  a  previous  iritis, 
also  with  pigmentation  from  old  skin  lesions.  Other  children  may  present  all  the 
manifestations  of  the  disease  at  birth.  Jlore  commonly  the  infant  is  born  healthy 
and  strong,  but  develops  signs  of  the  disease  within  three  months. 

Should  no  signs  appear  within  this  time,  the  child  must  not  be  regarded  as 
free,  for  they  may  not  develop  until  puberty  or  later,  i.e.,  late  congenital  .sjrphilis. 


262  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

The  later  the  s_yDij)toms  appear  after  birth,  the  better  the  prognosis,  so  far  as  life 
itself  is  concerned ;  for,  whereas  the  early  signs  are  invariably  general,  the  late 
are  local,  i.e.,  affection  of  bones,  or  ej'es,  etc.  So  far  as  the  effects  of  treatment 
are  concerned  the  prognosis  is  not  so  good  in  late,  as  it  is  in  early  congenital  syphilis, 
as  the  following  very  interesting  case  shows  : — 

Case  45. — A  man,  aged  36,  developed  bilateral  interstitial  keratitis,  he  had 
fissm-es  around  the  mouth,  and  well-marked  Hutchinson's  teeth.  He  had  seven 
injections  of  salvarsan,  without  any  improvement.  Mercury  was  prescribed 
for  one  year,  and  during  this  time  the  eye  symptoms  vanished,  but  patient 
became  deaf  in  both  ears.  In  spite  of  still  further  treatment,  with  salvarsan  and 
mercury,  patient  became  stone  deaf,  and  developed  arthritis  in  both  his  knee 
joints. 

Early  symptoms  are  marasmus  and  a  dry  and  wrinkled  skin,  with  Httle  or  no 
subcutaneous  fat ;  the  hair  is  short  and  the  nails  undeveloped,  the  nasal  bridge 
depressed,  the  voice  weak,  and  the  little  patient  snuffles  and  has  a  peculiar 
cry. 

Skin. 

The  skin  lesions  of  congenital  syphiUs,  like  those  of  the  acquired  form, 
consist  of  macular,  papular,  and  pustular  rashes.  In  both  cases,  the  rash  affects 
the  whole  body,  but,  in  congenital  syphilis,  it  shows  a  marked  predilection  for  the 
palms  of  the  hands  and  soles  of  the  feet ;  so  characteristic  do  some  authors  regard 
this,  that  they  state  that  papules  found  in  these  situations  can  be  safely  regarded 
as  syphilitic,  and  that  their  absence  is  evidence  that  an  eruption  is  non-syphiUtic. 
In  spite  of  the  commonly  entertained  opinion  to  the  contrary,  a  rash  on  the  buttocks 
is  not  absolutely  diagnostic  of  syphilis,  being  more  usually  due  to  the  use  of  dirty 
napkins  ;  adjacent  surfaces  that  rub  against  the  buttocks — the  backs  of  the  thighs, 
the  calves  of  the  legs,  and  the  heels — are  similarly  affected. 

The  non-syphilitic  erji^hemata  are  always  of  a  bright  red,  inflammatory  colour, 
while  the  rashes  of  congenital  syphilis  have  a  marked  brownish  tint,  and  ar6  often 
very  pronounced  in  the  flexures,  where,  owing  to  continuous  friction,  the  horny 
layer  is  rubbed  ofE  and  the  surface  eroded. 

The  presence  of  ulcers  does  not  necessarily  indicate  s^'phihs,  for  the  erythemata 
may  become  ulcerated  ;  and  sometimes  deep,  punched  out  iilcers,  resembhng 
gummata,  are  found — the  so-called  ecth}nna  or  vaccinifomi  dermatitis.  To  avoid 
a  wrong  diagnosis,  one  should  always  bear  in  mind  Kaposi's  axiom,  that  a  poly- 
morphic skin  eruption  on  a  baby  is  diagnostic  of  congenital  syphilis  ;  for  example, 
the  presence  of  a  macular  rash  on  the  face  or  other  parts  of  the  body,  and  of  a 


CONGENITAL   SYPHILIS.  263 

papular  rash  on  the  pahiis  and  soles,  will  go  far  to  establish  the  syphilitic  nature  of 
a  doubtful  rash  on  the  buttocks. 

Seborrhoeic  dermatitis  is  frequently  mistaken  for  a  syphilitic  rash,  but  in  the 
former  the  scalp  is  invariably  dry  and  scurfy,  and  the  mother  is  usually  suffering 
from  seborrhoea. 

A  congenital  syphilitic  roseola  is  practically  unknown.  The  commonest 
congenital  syphilide  consists  of  macules  distributed  over  the  whole  body,  and 
well  marked  on  the  face  and  head.  On  the  face,  the  eruption  is  not  infrequently 
orbicular. 

The  papular  syphilide  affects  chiefly  the  genitals,  anus,  palms  of  the  hands, 
and  soles  of  the  feet,  at  the  same  time  as  the  macular  syphilide  is  present  on  the 
trunk.  The  papules  may  coalesce,  and  the  surface  may  become  scaly  or  eroded  ; 
the  erosions  or  rhagades  occurring  at  the  corners  of  the  mouth  leave,  after  healing, 
those  radial  scars  so  suggestive  of  congenital  syphilis.  Linear  scars  are  also  found 
along  the  lower  lip — a  point  of  some  importance,  since  rhagades  at  the  corners  may 
occur  after  any  acute  illness.  Fissures  are  not  infrequently  found  beside  the  nose 
and  around  the  anus.     Peeling  of  the  palms  is  a  iiseful  diagnostic  sign. 

Condylomata  are  found  around  the  anus,  and  more  rarely  in  the  mouth  ;  they 
do  not  usually  make  their  appearance  until  the  child  is  some  months  old,  often  a 
year  or  more  ;  as  a  rule,  the  rash  has  disappeared,  and  their  presence  denotes 
absence  or  inadequacy  of  treatment. 

The  pustular  syphihde  is  the  Pemphigus  syphiliticus  Jieonatormn  of  the  older 
writers  ;  it  is  seldom  found  alone,  for  it  is  ahnost  invariably  accompanied  by  a 
maculo-papular  rash.  The  typical  papules  on  the  pahns  and  soles  confinn  the 
diagnosis,  and  serve  to  distinguish  the  syphilitic  pemphigus  from  the  streptococcal 
variety  of  Pemphigus  neonatorum.  When  found  alone,  however,  it  is  usually 
limited  to  the  palms  and  soles. 

Syphilitic  pemphigus  is  generally  present  at  birth,  although  it  may  develop 
later,  but  seldom  after  the  first  few  days. 

The  streptococcal  pemphigus  always  appears  after  birth,  and  is  really  a  form 
of  impetigo,  impetigo  being  usually  found  in  some  other  member  of  the  family  ; 
it  does  not,  as  a  rule,  attack  the  palms  and  soles.  Further,  a  child  with  syphilitic 
pemphigus  is  always  wasted,  and  looks  to  be  at  death's  door,  while  a  child  with 
streptococcal  pemphigus  looks  fat  and  cheerful.  The  former  disease  generally  ends 
fatally,  while  the  latter  responds  readily  to  weak  antiseptic  baths. 

Gummata  are  occasionally  seen,  but  do  not  in  any  way  difEer  from  the  acquired 
form.  Cases  have  also  been  described  of  symmetrical  gangrene,  with  and  without 
haemoglobinuria,  occurring  in  children  after  2  vears  of  age. 


264  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

It  is  still  opeii  to  question,  whether  the  cases  of  purpura  which  have  been 
described  as  occurring  in  congenital  syphilis,  usually  between  the  ages  of  5  and 
10  years,  are  really  specific  in  nature. 

The  nails  are  not  exempt,  and  syphilitic  onychia  is  by  no  means  uncommon. 
The  matrix  becomes  inflamed,  and  the  nail  over  it  loses  its  gloss  and  becomes 
irregular  on  the  surface  ;  the  whole  nail  is  gradually  shed,  and,  unless  mercurial 
treatment  is  given,  the  new  nail  will  likewise  sufier.  The  bullae  of  pemphigus 
may  afEect  the  matrix,  the  nail  being  raised  off  its  bed,  and  undermined  by 
sero-pus. 

Diffuse  Defluvium  capillitii  is  not  uncommon  in  congenital  syphihs.  Some 
children  are  born  without  any  hair  on  the  head,  but  such  an  occurrence  is  distinctly 
rare. 

The  lanugo  hair  often  persists  longer  than  usual ;  when  it  disappears,  the 
scalp  is  left  bald  or  sparsely  covered,  since,  owing  to  the  malnutrition,  the  new 
hair  does  not  grow. 

The  alopecia  may  afEect  the  eyebrows  also.  Indeed,  thinning  of  the  eyebrows, 
in  an  infant  a  few  months  old,  is  very  suggestive  of  syphihs. 

Teeth. 

Contrary  to  current  opinion,  the  primary  teeth  are  occasionally  affected. 
Still  recorded  a  case  of  the  primary  central  incisors  resembling  in  every  particular 
the  so-called  Hutchinsonian  teeth. 

The  permanent  teeth  show  marked  and  characteristic  changes,  especially  the 
incisor  teeth  of  the  upper  jaw,  which  are  shorter  and  smaller  than  normal  teeth  ; 
consequently  there  are  gaps  between  the  teeth,  and  when  the  mouth  is  closed  the 
teeth  of  the  upper  and  lower  jaws  do  not  meet ;  the  edges  are  not  parallel,  but 
conical  and  wedge-shaped.  The  free  border  is  thin  and  crescentic,  a  central  notch 
being  caused  by  lack  of  development  of  the  middle  tubercle.  The  lower  central 
incisors  not  rarely  present  changes.  They  may  resemble  the  incisors  of  thp  upper 
jaw,  but  more  often  they  are  rounded,  and,  in  their  upper  parts,  deficient  in  enamel, 
and  therefore  thin  and  rough.  The  canines  may  occasionally  be  notched,  and  the 
molars  are  not  infrequently  dome-shaped,  owing  to  the  maldevelopment  of  their 
tubercles. 

Bones. 

Bone  affections  in  congenital  syphilis  are  usually  late  signs  ;  but  changes 
in   utero   do   occur,  e.g.,  gummata   resulting  in  spontaneous  fractures.      Further, 


CONGENITAL   SYPHILIS.  265 

there  is  a  characteristic  boue  lesion  of  early  syphilis,  often  found  at  birth, 
called  by  its  discoverer — Wegner — Osteo-chondritis  sypJdlitica.  This  is,  in  the 
main,  an  epiphysial  disease,  which  affects  the  long  bones  and  ribs,  and  is  found 
in  almost  every  case  of  congenital  syphilis,  although  it  may  not  be  sufficiently 
pronounced  to  be  diagnosed  during  life.  Post-mortem,  it  is  perhaps  the  most 
valuable  sign  in  a  doubtful  case.  It  is  frequently  present  at  birth,  but  cannot,  as 
a  rule,  be  diagnosed  by  external  signs,  until  some  months  later.  It  reaches  its  acme 
at  the  age  when  rickets  is  common,  making  a  differential  diagnosis  extremely 
difficult.  The  incidence  of  this  condition  is  as  follows  :  it  is  most  marked  in  the 
lower  epiphysis  of  the  femur  ;  next,  in  the  lower  epiphyses  of  the  tibia,  ulna,  and 
radius,  upper  epiphyses  of  the  tibia,  femur,  and  fibula  ;  and  least  in  the  lower  end 
of  the  humerus.  The  increased  growth  leads  to  an  enlargement  of  the  epiphysis  ; 
as  a  sequel,  the  bone  involved  may  be  shortened  or  lengthened,  or  the  epiphysis 
may  be  separated  from  the  diaphysis.  The  separated  epiphysis  usually  unites 
again  with  the  shaft,  and  no  permanent  disfigurement  ensues. 

Separation  of  an  epiphysis  gives  rise  to  a  chain  of  symptoms,  to  which 
the  term  pseudo-paralysis  is  frequently  applied.  In  such  a  case,  if  the  afiected 
limb  be  raised  and  dropped,  it  falls  as  if  paralysed ;  spontaneous  move- 
naents  are  impossible,  but  muscular  action  persists ;  pressure  and  movement  are 
painful. 

According  to  Schmidt,  the  pathological  changes  which  result  in  a  separation 
of  the  epiphysis  are,  first,  an  increase  in  width  of  the  medulla,  in  which  the  cartilage 
cells  disappear  and  become  absorbed  by  the  blood-vessels  and  the  medullary  tissue  ; 
and,  subsequently,  a  growth  of  granulation  tissue  between  the  diaphysis  and  the 
epiphysis.  It  was  held  that  this  granulation  tissue  originated  from  the  bone  marrow 
of  the  diaphysis,  but  Schmidt  showed  it  to  be  a  richly  cellular  connective  tissue, 
containing  an  extraordinary  number  of  blood-vessels,  which  are  shut  off  from  the 
diaphysis,  but  communicate  with  the  vessels  of  the  perichondrium,  from  which 
they  originate. 

In  consequence  of  the  syphilitic  infection,  this  connective  tissue  increases  in 
growth,  and  takes  on  the  character  of  granulation  tissue.  Thereby  the  canals 
are  widened.  In  this  connective  tissue  growth,  there  is  an  attempt  at  bone  forma- 
tion, from  the  cartilage  cells  included  m  it.  The  process  increases  towards  the 
diaphysis,  so  that  in  time  the  cartilage  which  should  next  ossify  is  completely 
destroyed,  being  pushed,  so  to  speak,  into  the  marrow  of  the  diaphysis,  to  become 
the  prey  of  the  blood-vessels  and  marrow  cells  therein  ;  further,  the  granulation 
tissue  forms  a  barrier  which  prevents  ossification  of  the  cartilage  cells  above ;  and, 
in  consequence,  separation  of  the  epiphysis  follows. 


266  THE   BI0L0C4Y,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

The  most  characteristic  feature  to  the  naked  eye,  in  a  longitudinal  section  o-f 
the  diseased  epiphysis,  is  the  appearance  of  a  yellow  line,  often  zigzag,  between 
the  epiphysis  and  the  diaphysis. 

Besides  the  changes  described  above,  there  is  usually  some  thickening  of  the 
periosteum,  and  osteophytic  growths.  Osteo-periostitis  is  a  manifestation  of  late  con- 
genital syphilis,  and  shows  itself  in  various  ways.  For  instance,  in  the  fingers  and 
toes,  the  phalanges  are  enlarged  in  a  spindle-shaped  manner,  the  result  of  an 
ossifying  periostitis  of  the  shafts — Dactylitis  syphilitica. 

The  same  condition  may  also  affect  long  bones,  most  frequently  the  tibiae, 
especially  on  their  anterior  surfaces.  New  bone  forms,  as  the  result  of  the  inflam- 
mation, and  either  gives  rise  to  a  spindle-shaped  swelling  or  to  nmltiple  swellings 
• — nodes. 

Ossifying  periostitis  or  pericranitis  affects  both  the  parietal  and  frontal 
eminences,  causing  prominences  known  as  Parrot's  nodes,  and  giving  a  natiform 
or  "  hot-cross-bun  "  appearance  to  the  calvarium. 

Syphilitic  inflammation,  if  secondarily  infected  with  septic  organisms,  may 
result  in  necrosis  and  caries  of  bones,  especially  in  the  case  of  the  hard  palate,  jaws, 
nasal  bones,  and  cranium,  and  may  lead  to  perforation.  Perforation  of  the  palate  is 
especially  diagnostic  of  syphilis,  in  both  the  acquired  and  congenital  forms. 

True  gummata  may  affect  any  of  the  bones,  as  in  acquired  syphilis,  but  those 
occurring  on  the  slcuU  do  not  usually  pierce  the  pericranium  or  the  dura  mater. 

Rarefaction  of  bones — osteo-porosis — may  also  occur,  and  may  lead  to  multiple 
fractures.  Parrot  described  a  "  gelatinous  "  atrophy  which  affects  the  skull  bones, 
in  particular  the  occipital,  giving  rise  to  the  softening  known  as  craniotabes. 
Premature  synostosis  of  the  sutures  of  the  skull  not  infrequently  occurs,  and  is 
supposed  to  be  a  cause  of  idiocy;  or  their  patency  may  be  abnormally  prolonged. 

Hydrocephalus  occurs  in  congenital  syphilis,  but  is  not  common.  It  is  usually 
due  to  a  lepto-  and  pachymeningitis. 

Osteo- chondritis  syphilitica  is  an  early  manifestation,  while  usually  the  other 
bone  changes  occur  much  later.  ' 

The  bone  changes  above  described  are,  for  the  greater  part,  also  met  with  in 
rickets.  So  closely  do  rickets  and  congenital  syphilis  simulate  one  another,  that 
formerly  they  were  generally  believed  to  be  one  and  the  same  disease — an  opinion 
held  until  it  was  proved  that  rickety  children  could  acquire  syphilis.  There  is  no 
doubt  that  congenital  S3q)hilis  predisposes  to  rickets,  and,  although  the  two  diseases 
are  quite  distinct,  some  of  the  lesions  produced  by  either  are  indistinguishable 
during  life. 

As  a  result  of  osteo-chondritis,  hydrarthrosis  may  supervene. 


CONGENITAL   SYPHILIS.  267 

Occasionally  a  joint  becomes  filled  with  pus  ;  when  this  occurs  the  condition 
is  almost  invariably  symmetrically  bilateral. 

A  chronic,  bilateral,  painless,  symmetrical  hydrarthrosis,  usually  of  the  large 
joints,  the  knees  being  most  commonly  affected,  is  very  frequently  due  to  congenital 
S3rphihs. 

An  arthritis  simulating  a  tubercular  joint,  with  as  much  wasting  of  the 
muscles  as  is  typical  of  the  so-called  Tumor  albus,  may  also  be  met  with  in  con- 
genital syphilis.     It  may,  moreover,  occur  at  any  age. 


Vascular  System. 

The  heart  is  rarely  affected.  Both  diffuse  myocarditis,  secondary  to  an 
endophlebitis,  and  periphlebitis  or  arteritis  of  the  small  vessels,  and  gummata  in 
the  heart  muscle,  have  been  described.  The  gummata  are  small,  multiple,  and  to 
the  naked  eye  appear  as  white  spots. 

Changes  in  the  small  vessels  are  all  important,  since  there  is  no  syphilitic 
manifestation  which  is  not  primarily  dependent  on  such  changes.  In  no  way  do 
they  differ  from  those  occurring  in  the  acquired  form,  namely,  round-celled  infiltra- 
tion of  the  media  and  adventitia,  Endarteritis  obliterans,  etc.  Veins  are  not 
uncommonly  affected  in  congenital  syphilis.  A  marked  dilatation  of  the  super- 
ficial veins  is  often  seen,  and  there  is  no  doubt  that  syphiUs  is  often  the  cause  of 
varicose  veins  in  children  and  young  adults.  Aneurysms  may  be  met  with  in 
congenital  syphilis.  I  once  saw  a  case  of  syphilitic  aortic  aneurysm  in  a  girl, 
aged  15,  and  I  have  had  a  case  of  syphilitic  hemiplegia  in  a  boy,  aged  8. 


Mucous  Membranes. 

Catarrh  of  the  mucous  membrane  of  the  nose,  causing  coryza,  the  so-called 
"  snuffles,"  is  a  very  frequent  manifestation.  It  may  be  the  first  sign,  and  it  is 
a  persistent  one.  The  probability  is,  that  the  lesion  commences  in  the  submucous 
tissue.  Ulceration  and  involvement  of  the  underlying  periosteum  and  bone  not 
infrequently  occur,  causing  falling-in  of  the  bridge  of  the  nose,  and  thus  producing 
the  so-called  "  saddle-nose." 

Papules,  erosions,  and  ulcers,  may  also  affect  the  mucous  membranes  of 
the  lips,  cheeks,  and  tongue,  but,  with  the  exception  of  ulceration  of  the  hard 
palate  and  jaw  bones,  they  are  more  common  in  acquired  than  in  congenital 
syphilis. 


268  the  biology,  clinical  aspect  and  treatment  of  syphilis. 

Lungs. 

One  or  both  lungs,  either  as  a  whole  or  in  part,  may  show  the  characteristic 
white  pneumonia  of  Virchow.  An  affected  lung  is  large,  and  has  impressions 
of  the  ribs  on  its  surface  ;  on  section,  it  is  white  or  greyish.  The  chief  changes 
are  a  growth  and  desquamation  of  the  alveolar  epithelium,  with  considerable 
cellular  infiltration  and  hyperplasia  of  connective  tissue.  This  is  the  true  "  white 
pneumonia,"  and  is  generally  said  to  be  incompatible  with  life. 

Carpenter  reports  a  case  in  which  death  did  not  occur  until  the  age  of  13 
months.  Still  considers  that  the  condition  is  consistent  with  much  longer  life, 
and  that  it  is  the  cause  of  the  fibroid  disease  of  one  lung  which  is  by  no  means 
an  uncommon  disease  in  children. 

A  second  form,  usually  described  as  interstitial  pneumonia,  is,  as  its  name 
implies,  dependent  upon  a  growth  of  the  interalveolar  and  interlobular  connective 
tissue,  which  starts  from  the  vessels  and  bronchi.  Owing  to  this  connective  tissue 
growth,  the  alveoli  become  compressed.  Such  a  lung  is  enlarged,  pale,  or  greyish- 
red,  and  hard. 

The  capillaries  are  often  enlarged,  and  tortuous  ;  the  alveolar  epithelium 
is  swollen,  and  may  show  desquamation,  but  more  often  it  assumes  a  cubical 
character,  the  lung  alveoli  presenting  the  appearance  of  glandular  spaces.  A  com- 
bination of  the  white  pneumonia  with  interstitial  overgrowth  is  the  most  common 
appearance  in  the  lungs  of  syphilitics. 

Digestive  Tract. 

The  intestinal  canal  may  be  the  seat  of  ulcers,  which  are  gummatous  in 
nature,  and  which  occur  most  commonly  in  the  small  intestine.  Multiple  miliary 
gummata  are  also  met  with  in  the  mucous  and  muscular  coats,  from  the  stomach 
downwards.  Bowel  lesions  are  more  common  in  congenital  than  in  acquired 
syphilis. 

Liver.  , 

The  liver  is  very  frequently  found  diseased  in  children  who  are  born 
dead.  Jaundice  and  ascites  are  rare  complications.  The  liver  is  usually  enlarged. 
The  surface  is  commonly  unaltered,  except  in  the  contracted  hob-nail  tjYie  of 
cirrhosis,  which  is  found  in  later  childhood. 

Hochsinger  describes  four  varieties  of  hepatic  changes  : — 

1.  Diffuse,  small,  round-celled  infiltration  of  the  connective  tissue,  and 
involvement  of  the  acini  by  these  cells.  The  inflammation  starts  around  the  small 
arteries.     The  macroscopic  appearance  of  the  liver  is  normal. 


CONGENITAL    SYPHILIS.  2G9 

2.  H3'perplasia  of  the  connective  tissue,  so  that  the  liver  is  enlarged,  hard  in 
consistence,  and  yellow  or  yellow-brown  in  colour.  The  commencement  is  a  hyper- 
plasia of  the  connective  tissue  in  the  adventitia  of  the  vessels. 

3.  Miliary  gummata  (flint-like  liver),  greyish-yellow  nodules  about  the  size  of 
a  pin's  head,  are  scattered  about,  in  the  parench^mia  chiefly,  but  also  in  the 
interacinous  connective  tissue,  and  especially  around  branches  of  the  portal 
vein. 

4.  True  gummata.     A  rare  condition. 

The  most  typical  hepatic  condition  found  in  infants  is  a  combination  of  the 
first  and  second  of  the  varieties  described  by  Hochsinger.  The  liver  may  be 
enlarged  and  hard,  but  the  surface  remains  smooth,  or  very  slightly  granular  ; 
there  is  a  diffuse  pericellular  cirrhosis,  the  newly  formed  connective  tissue  being 
both  cellular  and  vascular.  The  liver  cells  are  isolated  by  this  newly  formed  tissue 
into  small  groups  of  one,  two,  three,  or  four  cells.  The  Spirochaeta  pallida  may 
be  demonstrated  in  considerable  numbers,  in  this  form  of  the  disease. 

In  Hochsinger's  third  variety,  there  is  often  marked  fibrosis  in  the  neighbour- 
hood of  the  gummata.  Large  gummata — the  true  gummata  of  Hochsinger's  fourth 
variety — are  less  common  in  the  congenital  than  in  the  acquired  form  of  the  disease. 
Amyloid  degeneration  of  the  connective  tissue  stroma  may  occur. 

Besides  the  usual  forms  of  Hepatitis  interstitialis  et  gummosa,  Schiiffel 
described  a  condition  peculiar  to  congenital  .syphilis,  and  he  called  this  Peripyle- 
jMehitis  syphilitica.  This  is  characterised  by  enlargement  of  the  liver,  which  is 
of  a  brown-green  colour,  and  flabby.  Throughout  the  soft  parenchjana,  the  larger 
branches  of  the  portal  vein  can  be  felt  as  hard  cords,  about  the  thickness  of  a  little 
finger.  Cross-section  of  a  cord  shows  the  lumen  of  the  vein  narrowed,  the  bihary 
■ducts  and  branches  of  the  hepatic  artery  shut  in  and  constricted  by  fibrous 
tissue.  The  change  depends  upon  an  excessive  fibrous  tissue  increase  of  Glisson's 
capsule. 

The  disease  aSects  either  of  the  chief  branches  of  the  portal  vein,  and  stops 
short  at  the  sinus  venae  porta;. 

The  umbihcal  vein  is  intact.  Jaundice,  colourless  faeces,  meteorism,  ascites, 
enlargement  of  the  .spleen,  and  intestinal  haemorrhages  are  the  cUnical  symptoms. 

Pancreas. 

This  organ  may  be  afiected  by  a  chronic  interstitial  inflammation,  leading  to 
enlargement,  and  also  by  gummata. 


270  the  biology,  clinical  aspect  and  treatment  op  syphilis. 

Kidneys. 

Interstitial  nephritis  is  the  commonest  manifestation  of  this  disease,  and  it  is 
not  infrequently  associated  with  amyloid  degeneration.  True  gummata  are  very 
rare. 

SUPEARENALS. 

Virchow  and  Barensprung  describe  the  suprarenals  as  being  enlarged, 
dotted  with  small,  scattered,  yellowish-white  nodules,  and  as  showing  marked 
fatty  changes  in  the  parenchyma.  Sj^hilis  may  also  be  the  cause  of  some  of  those 
cases  in  which  blood  cysts  are  found. 

Testicles. 

Gummata  are  extremely  rare,  but  diffuse  interstitial  inflammation  is  not 
uncommon ;  usually  occurring,  as  it  does,  within  the  first  few  months,  it  is 
pathognomonic  of  syphiHs  ;  the  epididpiiis  may  or  may  not  be  affected,  and  an 
accompanying  hydrocele  is  rare.  In  consequence  of  this  connective  tissue  hyper- 
plasia, there  is  a  growth  and  degeneration  of  the  glandular  epithelium. 

Syphilitic  affections  of  the  female  sexual  organs  are  extremely  rare.  Besides  the 
usual  interstitial  changes,  which  differ  in  no  way  from  those  observed  in  other 
organs,  Schukowsky  reported  an  interesting  case  of  Metrorrhagia  neonatorum, 
which  was  caused  by  an  Endarteritis  obliterans  of  the  vessels  in  the  fundus  uteri. 

Spleen. 

Enlargement  of  the  spleen  is  common  in  cases  of  congenital  syphihs,  and  is 
most  obvious  when  the  child  is  IJ  or  2  years  old.  It  is  difficult  in  many  of 
these  cases  to  decide  whether  syphihs  or  rickets  is  the  proximate  cause  of  the 
enlargement.  Parrot  recognised  two  forms  of  enlargement — one  resulting  from  a 
chronic  h}rperaemia  due  to  stasis  in  the  portal  circulation,  the  other  due  to  a  true 
hyperplasia  of  the  connective  tissue  in  the  gland  and  in  the  capsule.  Still  reported 
two  cases  of  gummata  of  the  spleen,  but  the  condition  is  extremely  rare. 

Thymus. 

This  gland  is  here  mentioned,  since  an  affection  of  it  has  been  described 
as  being  diagnostic  of  congenital  syphilis,  namely,  Dubois'  abscesses.  These  are 
single  or  multiple  abscesses,  found  in  the  gland  substance.  There  is  very  little 
evidence  that  they  are  definitely  syphilitic. 


congenital  syphilis.  271 

Central  Nervous  System. 

The  severe  forms  of  defective  development  of  the  central  nervous  system  are 
characteristic  of  congenital  syphilis — naturally  the  infant  is  either  born  dead,  or 
it  dies  a  few  days  after  birth.  It  is  not  at  all  uncommon  for  one  cerebral  hemisphere 
to  be  much  smaller  than  the  other,  and  yet,  as  far  as  one  can  tell,  the  functional 
activity  of  each  is  the  same.  A  marked  asymmetry  of  the  head  and  face  accompanies 
this  deformity.  I  had  such  a  case  quite  recently,  in  a  boy,  aged  11  ;  beyond  a 
high  myopia  and  a  positive  Wassermann  reaction,  nothing  abnormal  could  be 
detected ;  and  the  boy's  intelligence  and  knowledge  was  very  much  in  advance 
of  his  years. 

Hydrocephalus  is  sometimes  caused  by  syphilis,  and  its  pathology  is  not  in 
all  cases  the  same.  In  some  cases,  it  is  highly  probable  that  the  condition  is  due 
to  an  early  syphilitic  arteritis.  This  has  resulted  in  a  pronounced  exudation  of 
lymph,  which,  in  accumulating,  distends  the  ventricles  and  the  central  canal  of  the 
cord.  On  the  other  hand,  and  more  frequently,  the  condition  is  due  to  a  severe 
involvement  of  the  meninges. 

A  child  may  develop  hydrocephalus  m  utero,  or  not  until  after  birth — if  the 
latter,  never  later  than  the  first  year. 

In  many  cases,  the  condition  is  associated  with  nervous  symptoms. 

A  localised  gumma,  or  miliary  gummata,  may  affect  any  part  of  the  brain  and 
cord,  and  diffuse  gummatous  pachymeningitis  and  leptomeningitis  is  well  known. 
As  in  acquired  syphilis,  the  brain  is  more  frequently  involved  than  the  cord,  except 
in  the  true  degenerative  lesions,  when  the  lesion  is  generally  a  mixed  one.  There 
is  no  doubt  now  that  congenital  syphilis  may  cause  degenerative  myelitis,  in  which 
the  symptoms  do  not  differ  from  those  met  with  in  the  adult  form.  Most  congenital 
syphilitic  degenerative  lesions  do  not  give  rise  to  symptoms  until  the  child  is  about 
eight  years  old,  or  older.  Degenerative  lesions  are  really  lesions  of  late  congenital 
syphilis,  and  may  not  manifest  themselves  until  the  patient  is  over  20  years  of 
age ;  hence  it  is  sometimes  quite  a  difficult  matter  to  be  sure,  when  one  is  dealing 
with  a  degenerative  nervous  lesion  in  a  patient  of  25  years  of  age,  whether  the  case 
is  one  of  acquired,  or  of  congenital  syphilis. 

According  to  Halbau  and  Dydynski,  optic  atrophy  and  sphincter  (bladder) 
paralysis  are  more  frequently  met  with  in  the  congenital  form  than  in  the  accpiired 
form  of  degenerative  m3^elitis,  while  severe  ataxia  is  rare.  Most  authorities  are 
now  agreed  that  Friedreich's  ataxia  is  never  of  syphilitic  origin. 

Degenerative  encephalitis  is  not  at  all  infrequently  met  with  in  congenital 
syphilis,  and  the  symptoms  do  not  differ  from  those  met  with  in  the  acquired  form. 

s 


272  THE   BI0L0C4Y,    CLINICAL   ASPECT   AND    TREATMENT   OF   SYPHILIS. 

As  a  rule,  the  patient  is  over  eight  years  of  age.  The  course  of  infantile  degenerative 
encephalitis  is,  on  the  average,  longer  than  that  met  with  in  adults.  According 
to  Alzheimer,  the  average  duration  is  aboiit  four  and  a-half  years.  In  the  majority 
of  cases,  inferior  mental  endowment  can  be  dated  back  to  infancy.  The  course 
the  case  runs  is  usually  one  of  a  simple  progressive  dementia,  and  the  depressive 
and  maniacal  states  so  commonly  witnessed  in  the  adult  form  are  very  frequently 
lacking. 

Actual  paralyses  are  more  common  in  the  congenital  form,  and,  as  already 
stated,  the  case  is  frequently  a  mixture  of  degenerative  myelitis  and 
encephalitis. 

The  more  thoroughly  every  congenital  syphilitic  is  examined,  the  more  fre- 
quently will  nervous  symptoms  be  found,  and,  as  is  the  case  in  acquired  syphilis, 
the  nervous  signs  and  symptoms  may  be  of  almost  any  nature,  both  meningeal 
and  arterial.  Generally  speaking,  the  nervous  diseases  of  congenital  syphilis  are 
more  often  of  ameningeal  origin,  while  in  acquired  syphilis,  they  are  more  often 
of  meningeal  origin.  Although  the  brain  is  more  frequently  involved  than  the 
cord,  cases  of  spastic  spinal  paralysis  are  undoubtedly  met  with  in  congenital 
syphihs,  and  sometimes  idiocy  is  associated  with  the  condition.  Diminished  intelli- 
gence, even  amounting  to  idiocy,  is  no  doubt  often  caused  by  syphilis,  but  it  is  almost 
impossible  to  state  accurately  the  rdle  which  syphilis  plays,  because  many  of  the 
cases  have  never  had  a  syphilitic  symptom,  nor  have  given  a  positive  Wassermann 
reaction.  Whether  the  idiocy  is  due  to  the  syphilis  itself,  or  occurs  only  because 
the  parents  have  had  syphilis,  is  not  at  present  known,  but  of  one  thing  I  am  quite 
sure,  and  that  is,  that  syphilis  is  far  more  often  blamed  in  this  class  of  case  than 
it  should  be. 

Again,  as  regards  epilepsy  in  children,  the  greatest  difference  of  opinion  exists 
as  to  whether  syphilis  is  a  potent  cause  or  not.  Sj'philis  should  always  be  con- 
sidered as  a  possible  cause,  for  the  simple  reason  that  most  cases  of  sj'philitic  origin 
do  so  well  under  treatment,  but,  according  to  my  own  experience,  syphilis  is  far 
from  being  a  common  cause  of  the  condition.  , 

Other  lesions  which  are  occasionally  met  with,  are  cranial  nerve  palsies,  which 
may  be  of  the  true  degenerative  t^^pe  or  secondary  to  a  basilar  meningitis. 

That  isolated  pupil  phenomenon,  to  which  I  particularly  called  attention 
in  acquired  syphilis,  ma}'  also  be  met  with  in  congenital  syphilis.  Mere  inequality 
of  pupils  should  not  be  invariably  diagnosed  as  sj'jjhilitic,  since  some  healthy 
people  are  born  with  unequal  pupils. 

Almost  a  characteristic  symptom  of  congenital  syphilis,  when  it  occurs,  is 
Diabetes  insipidus.     The  lesion  is  in  the  posterior  lobe  of  the  pituitary  body. 


congenital  syphilis.  273 

Eyes. 

Affections  of  tlie  eyes  are  extremely  common.  Changes  in  the  fundus 
oculi,  choroiditis,  and  iritis  may  occur  soon  after  birth,  or  they  may  be  strictly 
congenital.  The  patches  in  the  choroid  are  usually  iiTegular  in  shape  and  white 
in  colour,  with  dark,  pigmented  borders,  and  they  are  generally  associated  with 
vitreous  opacities.  Choroiditis  may  interfere  with  vision,  nystagmus  being  the 
first  sign  which  calls  attention  to  the  defect. 

Hutchinson  says  that  iritis  most  frequently  affects  females,  is  most  commonly 
seen  at  the  age  of  5  months,  and  is  often  bilateral ;  that  it  is  not  characterised  by 
the  inflammatory  phenomena  which  are  met  with  in  adult  iritis ;  and  that  it 
quickly  leads  to  occlusion  of  the  pupil,  but  is  extremely  amenable  to  mercurial 
treatment. 

The  characteristic  and  diagnostic  eye-change,  in  late  syj)hilis,  is  interstitial 
keratitis.  This  usually  appears  just  before  puberty,  affects  one  eye  first,  and  then 
usually  becomes  bilateral,  whether  the  patient  is  treated  with  mercury  or  not. 
Opaque  areas  appear  on  the  deep  surface  of  the  cornea,  and  fine  blood-vessels  which 
come  from  the  conjunctiva  and  sclerotic  run  on  and  into  its  substance.  The 
condition  may  last  for  months  or  years,  till  sight  is  almcst  lost ;  but,  however 
bad  the  case  may  be,  there  is  always  something  to  be  hoped  for  from  treatment. 
Mercurial  treatment  is  the  best ;  salvarsan  appears  to  have  no  action. 

Double  interstitial  keratitis  is  frequently  associated  with  Hutchinsonian  teeth 
and  nodes  on  the  tibiae — the  so-called  "  syphilitic  triad."  Any  of  these  eye  lesions 
may  appear  first  in  adult  life. 

Ears. 

In  infancy,  there  may  be  a  catarrh  of  the  external  auditory  meatus 
and  middle  ear,  but  it  is  in  no  wise  characteristic  of  syphilis.  In  the  late  form, 
usually  after  puberty,  there  occurs  an  insidious  inflammation  of  the  internal  ear, 
and  in  time  this  leads  to  complete  loss  of  hearing.  Syphilis  is  also  a  cause  of  deaf- 
mutism.  In  late  syphilis,  all  auditory  symptoms  appear  to  be  uninfluenced  by 
treatment,  and  in  my  experience  salvarsan  seems  to  aggravate  them. 

Lymphatic  Glands. 

In  congenital  syphilis,  the  lymphatic  glands  may  become  enlarged,  but  there 
is  never  a  general  enlargement  all  over  the  body,  as  is  the  case  in  acquired  syphilis ; 
one  group  becomes  enlarged,  but  not  from  any  ascertainable  cause.  So  rarely  are 
the  glands  affected,  that  enlargement  makes  one  suspect  acquired  syphilis. 

s2 


274  the  biology,  clinical  aspect  and  treatment  of  syphilis. 

Diagnosis. 

The  diagnosis  of  congenital  syphilis  is  made  too  often.  A  rash  on  the 
buttocks  seems  to  be  regarded  as  diagnostic  :  it  is  more  often  due  to  a  simple 
erythema  than  not.  A  macular  rash  on  the  face,  and  papules  on  the  palms 
and  soles,  are,  however,  pathognomic.  It  should  not  be  forgotten  that  "  snuffles  " 
is  often  due  to  a  simple  catarrh,  and  some  flattening  of  the  bridge  of  the  nose  is 
characteristic  of  all  infants.  Orchitis  and  pseudo-paralyses  are  most  important 
signs,  syphilis  being  the  only  cause  in  early  life.  Much  weight  cannot  be  laid  on 
enlargement  of  the  liver  and  spleen.  Enlargement  of  the  epiphyses  before  the 
first  year  is  diagnostic  of  syphilis.  In  a  doubtful  case,  an  ophthalmoscopic  examina- 
tion should  be  made. 

In  later  life,  Hutchinson's  teeth,  interstitial  keratitis,  and  periostitis  of  the 
tibiae  are  the  most  important  diagnostic  signs. 


Prognosis. 

Infants  born  with  manifestations  of  syphilis,  usually  die.  Death  is  the  rule 
in  cases  of  pemphigus.  In  degenerative  nervous  cases,  the  termination  is  almost 
invariably  fatal.  Children  born  healthy,  but  showing  signs  in  early  infancy,  if 
submitted  to  appropriate  treatment  for  a  full  period  of  two  or  three  years,  may 
perhaps  escape  subsequent  manifestations  altogether.  Children  who  have  late  signs, 
have  probably  often  been  free  in  early  life,  and  consequently  have  had  no  treatment. 
In  these  cases,  the  symptoms  often  remain  uninfluenced  by  treatment,  but 
ultimately  heal  up  of  their  own  accord.  The  amount  of  damage  done  will  depend 
upon  the  site  affected. 

General  Pathology. 

A  point  upon  which  a  good  deal  of  stress  should  be  laid,  is  the  appearance  of 
embryonic  areas  in  the  organs.  ' 

The  syphilitic  virus  affects  an  organ  before  it  is  mature  ;  since  its  action  is 
to  increase  the  formation  of  fibrous  tissue,  especially  of  the  vessels,  the  parenchyma 
of  the  organ  suffers  in  nutrition,  and  cannot  mature  so  quickly  as  it  would  other- 
wise have  done  ;  consequently,  at  or  after  birth,  it  may  in  parts  retain  embryonic 
characters.  For  instance,  the  foetal  liver  has  the  capacity  of  manufacturing 
blood,  a  function  which  normally  disappears  after  birth,  but  which  may  be  retained 
in  congenital  syphilis  ;  and  Schridde  describes  cases  showing  areas  where  both 
red  and  white  corpuscles  were  found  in  process  of  manufacture. 


CONGENITAL    SYPHILIS.  -'/O 

Spirochaetae  have  been  found  in  every  organ,  but  are  most  abundant  and 
most  frequenth-  found  in  the  connective  tissue  of  the  medulla  of  the  suprarenals. 
In  the  liver,  they  are  especially  found  in  the  neighbourhood  of  the  large  blood- 
vessels ;  and  in  the  lungs,  especially  around  the  vessels  in  the  walls  of  the  alveoli. 
I  have  found  the  phases  of  the  Leucocijtozoon  syphUidis  in  congenital  syphilitic 
liver,  lungs,  and  suprarenals,  but,  for  the  examination  to  be  successful,  the  tissue 
must  be  fixed  as  soon  after  death  as  possible. 

WORKS  CONSULTED. 

Bab.  (1907),  ''  Miinch.  med.  Woch."     liv,  2265. 

Fournier  (1886),  "La  Syphilis  H^reditaire  Tardive."     Paris. 

Xonne  (1909),  "  Syph.  u.  Xervensystem."     S.  Karger.     Berlin. 

Still  (1908),  "  Congenital  SjT^hili.s,"  in  D'Arcy  Power  and  Mvirphys  "  System  of  Syphilis."    i. 

Unna  u.  Jannus  (1906  u.  1907),  "  Dermat.  Jahresbericht."     ii-iii. 

Adamson  (1907),  "  The  Skin  Affect,  of  Childhood."     Oxf.  Med.  Press.      London. 

Hochsinger  (1904),  "  Studien  Uber  die  hereditare  Syphilis."    Wien. 

Hutchinson  (1901),  "  Syphilis."     Cassell  &  Co.     London. 


CHAPTER  XXVII. 

CHEMOTHERAPY  AND  ITS  MODE   OF  ACTION  IN  THE 
CASE  OF  SYPHILIS. 

The  Chemistry  of  Salvarsan  and  the  Action  to  be  Expected  from  its 

Composition. 

A  few  words  of  general  chemical  explanation  may  be  offered,  before  discussing 
the  chemical  nature  of  "  salvarsan  "  and  its  mode  of  action. 

A  monovalent  element  is  one  which  can,  under  suitable  conditions,  combine 
equimolecularly  with  one  element  of  similar  valency,  in  the  proportions  of  one  atom 
of  each.  Thus,  hydrogen  and  chlorine  are  monovalent  elements,  and  they  combine 
to  form  hydrogen  chloride,  or  hydrochloric  acid.  Their  valencies,  or  combining 
capacities,  are  then  satisfied. 

Di-,  tri-,  tetra-,  and  pentavalent  elements  can  combine  with  two,  three,  four, 
and  five  monovalent  elements  respectively  to  satisfy  their  combining  capacities. 
A  trivalent  element  may  combine  with  one  mono-  and  one  divalent  element,  and 
so  following,  for  elements  of  higher  valency. 

Carbon  is  a  tetravalent  element,  but  it  differs  from  other  elements  in  that  it 
can  link  up  with  other  carbon  atoms  to  form  stable  compounds.  The  result  of  this 
extraordinary  fact,  due  to  electro-chemical  inertia,  is  that  there  is  absolutely  no 
limit  to  the  number  of  carbon  compounds. 

In  benzene,  six  carbon  atoms  form  a  ring.  The  empirical  formula  of  tenzene 
is  CgHg.     The  graphical  formula  is  usually  wi-itten,  after  Kelnile  : — 

H 

I 
C 

•"^ 
H— C      C— H 

II       I 
H— C      C— H 

\// 
C 

i 
H 


CHEMOTHERAPY    AND   ITS    MODE    OF   ACTION    IN    SYPHILIS.  277 

For  the  sake  of  convenience,  this  compound  is  usually  represented  by  a  simple 
hexagon.  Arsenic  may  be  either  tri-  or  pentavalent,  and  it  is  exceedingly 
poisonous.  The  valencies  of  nitrogen  correspond  with  those  of  arsenic.  Arsenic 
is  an  element  on  the  border  line  between  metals  and  non-metals. 

Salvarsan  is  the  commercial  name  given  to  dioxydiaminoarsenobeuzol.  The 
constitutional  formula  of  this  body  is  ; — 

As  =  As 

n     n 

H.N    I       I  11   NK. 

OH  OH 

It  will  be  seen  that  it  contains  two  oxygen  atoms,  attached  to  separate  benzene 

rings  ;    two  amino  (NHo)  groups,  attached  to  separate  benzene  rings ;    and  two 

arsenic  atoms,  attached  to  separate  benzene  rings.     The  two  benzene  rings  are  linked 

together  by  the  two  arsenic  atoms.     This  body  has  several  interesting  properties  : — 

(i)  Arsenic  is  at  once  metallic  and  non-metallic  in  its  properties  ;  here  it  is 

trivalent,  but  it  may  be  pentavalent. 
(ii)  The  amino  (NH^)  group  is  basic  in  nature, 
(iii)  The  hydrogen  in  the  OH  group  is  acidic  in  nature. 

Here,  then,  we  have  a  body  which  is  at  once  acidic  and  basic,  or  amphoteric, 
and  it  also  contains  an  element  which  is  both  metallic  and  non-metallic,  and  which 
has  a  varying  valency.  The  body  is  insoluble  in  water,  and  on  this  account  the 
hydrochloride  of  the  body  was  prepared.     Its  formula  is  : — 


As  =  As 


C1H.H,N 


\/ 


V 


NH.,.HL'l 


OH  OH 

The  hydrochloride  dissolves  sparingly  in  water,  but  its  solution  is  strongly 
acid,  hence  it  is  not  very  suitable  for  intravenous  administration.  It  may  be 
injected  intravenously,  and  is  on  the  whole  more  potent  than  the  basic  solution 
prepared  from  it,  but  it  is  at  the  same  time  more  toxic. 

From  the  hydrochloride,  the  sodium  salt  is  prepared,  by  adding  sodium  hydrate 
to  the  acid  solution,  and  this  renders  it  more  soluble  in  water.  Therefore,  the  drug 
is  generally  administered  in  this  form.     The  formula  of  the  sodium  salt  is  : — 

As  =  As 


278  THE    BIOLOGY,    CLINICAL   ASPECT    AND    TREATMENT    OF   SYPHILIS. 

Comparing  this  formula  with  that  of  the  fundamental  substance,  it  will  be 
seen  that  the  two  OH  groups  have  been  replaced  by  ONa  groups.  The  OH  groups 
were  acidic  ;  the  ONa  groups  are  basic,  as  are  also  the  NH,  groups,  so  that  the 
compound  injected  is  distinctly  basic. 

A  nice  point  now  arises.  When  the  compound  is  injected,  does  it  remain 
basic,  or  does  it  become  amphoteric  ?  In  other  words,  are  the  ONa  groups  replaced 
by  OH  groups  ?  One  cannot  give  a  definite  reply  to  this  question,  because  the 
precise  chemical  composition  of  the  body  fluids  is  not  known.  We  do,  however, 
know  that  the  blood  tends  to  maintain  a  definite  standard  of  alkalinity.  We 
know,  too,  that,  if  this  standard  be  disturbed,  the  blood  will  proceed,  with  almost 
inconceivable  rapidity,  to  re-establish  its  standard.  Now,  therefore,  if  an  alkaline 
compound  be  injected  into  the  body,  the  blood  will  at  once  reduce  the  alkalinity 
of  that  compound.  In  the  case  of  the  sodium  compound  which  we  are  considering, 
this  can  only  be  done  by  converting  the  ONa  groups  into  OH  groups,  with  the 
formation  of  neutral  sodium  salts.  That  is  to  say,  an  alkaline  ONa  group  is 
converted  into  an  acid  OH  group,  with  the  formation  of  a  neutral  sodium  salt,  so 
that  the  final  result  is  a  reduction  in  the  total  alkalinity  of  the  compound  injected. 

To  what  does  this  lead  ?  To  the  highly  important  fact  that  now  we  again  have 
the  original  base  -substance,  which  is  amphoteric,  by  reason  of  its  possession  of 
basic  NHj  groups  and  acidic  OH  groups.  The  importance  of  this  fact  consists  in 
the  point  that  such  an  amphoteric  compound  will  be  ready  to  attack  either  acidic 
or  basic  compounds.  Reference  to  the  chapter  on  the  chemistry  of  the  Leucocytozoon 
syphilklis  will  show  proof  of  the  fact,  that  some  phases  in  the  life-cycle  of  that 
organism  are  more  basophilic,  and  that  some  are  more  acidophilic  than  others. 
It  is  therefore  possible  that  reaction  between  these  phases  and  the  amphoteric 
salvarsan  plays  a  r6le  in  the  action  of  the  drug  upon  the  syphilitic  organism. 

It  may  be  objected  to  this  line  of  argument,  that  the  only  active  principle  in 
salvarsan  is  the  arsenic,  and  that  the  other  facts  are  irrelevant,  and  this  is  a  view 
which  is  very  largely  held. 

Let  us  consider  the  action  of  the  arsenic.  In  the  fii'st  place,  the  arsenic  will 
exert  no  action,  until  it  has  been  freed  from  the  compound.  An  amphoteric 
compound  will  tend  to  break  down  when  it  comes  in  contact  with  either  a  basic  or 
an  acidic  substance.  Therefore,  the  arsenic  will  tend  to  be  set  free  for  action  in 
contact  with  the  Leucocytozoon  syphilidis ;  hence  the  great  activity  of  the  drug 
against  the  organism.  It  is,  therefore,  fair  to  conclude  that  salvarsan  is  particularly 
well  fitted  to  apply  its  arsenic  at  the  most  necessary  point. 

In  the  second  place,  consider  the  action  of  the  arsenic.  The  arsenic  is  excreted 
unchanged.     That  is  to  say,  it  is  trivalent  when  injected,  and  it  is  also  trivalent 


CHEMOTHERAPY   AND   ITS   MODE    OF   ACTION   IN    SYPHILIS.  279 

when  excreted.  To  what  conclusion  does  this  lead  us  ?  To  the  conclusion  that 
the  arsenic  acts  as  a  catalytic  agent.  In  what  way  can  the  arsenic  act  as  a  catalyst  ? 
In  all  probability  it  acts  as  an  oxygen  carrier — in  other  words,  as  an  activator  of 
oxydase  ferments. 

Finally,  then,  we  may  state  that,  from  a  study  of  the  chemical  formula  alone, 
salvarsan  might  be  expected  to  destroy  the  Leucocytozoon  syphilidis  in  the  following 
ways : — 

(i)  The  basic  portion  takes  up  the  acidic  phases  of  the  organism. 

(ii)  The  acidic  portion  takes  up  the  basic  phases  of  the  organism. 

(iii)  The  catalytic  action  of  the  arsenic,  set  free  in  the  two  above-mentioned 
reactions,  destroys  the  organism  by  oxidation. 

(iv)  Salvarsan  also  is  a  reducing  agent,  and  it  may  well  exert  action  in  this 
direction. 

Neo-Salvarsan. 

Neo-salvarsan  is  the  commercial  name  for  sodium-dioxydiamino-arsenobenzene- 
mono-methane-sulphonate,  and  its  formula  is  : — 

As 


OH 

Salvarsan  was  the  606th  body  investigated,  and  neo-salvar.san  was  the  914th. 
It  is  obtained  by  the  action  of  formaldehyde  sulphoxalate  upon  "  606."  It  is 
rather  surprising  that  307  preparations  were  made  before  neo-salvarsan  was  tried, 
for  it  is  well  known  that  the  addition  of  an  SO.;H  group  is  a  great  aid  in  preparing 
a  soluble  body.  The  base  dioxydianunoarsenobenzol  was  the  592nd  preparation 
tried — salvarsan  is  the  hydrochloride  of  this  base — and  it  was  the  606th  preparation 
tried.  Again,  it  is  a  matter  for  some  surprise  that  thirteen  preparations  were  made 
before  the  hydrochloride  was  investigated.  One  may  safely  say  that  ninety-nine 
chemists  out  of  a  hundred  would  prepare  the  hydrochloride  of  a  base  immediately 
after  preparing  the  base,  and  the  same  percentage  would  have  immediately  added 
an  SO3H  group,  if  they  wanted  to  make  the  body  soluble.  The  marked  advantage 
possessed  by  "  914"  over  "  606  "  is  the  greater  solubility  of  the  former.  When 
a  body  is  to  be  injected  in  solution,  the  advantage  of  ready  solubility  is  obvious. 
Both  these  bodies  have  a  great  affinity  for  oxygen,  and  they  must,  therefore,  be 
kept  in  an  inert  gas. 


280  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT    OF   SYPHILIS. 

Now,  let  us  consider  the  therapeutic  action  of  these  two  bodies,  and  let 
us  see  if  the  difference  in  action  can  be  explained  by  their  differences  in  chemical 
constitution. 

The  difference  in  action  of  these  two  drugs  is,  that  "  914  "  is  less  potent  than 
"  606,"  though  the  dosis  tolerata  of  the  former  is  greater  than  that  of  the  latter. 
The  actual  weight  of  arsenic  injected  is  greater  in  the  case  of  "  914  "  than  in  that 
of  "  606."  In  the  case  of  salvarsan  the  arsenic  content  per  cent,  is  31 '56,  while  in 
neo-salvarsan  it  is  32 "10.  We  therefore  must  conclude  that  arsenic  is  not  the 
greatest  factor  in  destroying  the  organism  of  syphilis. 

As        =         As  As        =        As 


H,N 


\y 


\y 


\^ 


ONa  ONa  OH  OH 

Salvarsau.  Neo-salvarsan. 


NH.CH.,O.SONa 


The  above  formulae  represent  the  composition  of  the  compounds,  as  injected. 
The  arsenic  has  been  already  considered. 

"606"  contains  two  basic  ONa  groups,  and  "914"  contains  two  acidic  OH 
groups.  "606"  contains  two  basic  NHg  groups;  "914"  contains  one  NHj  group 
and  one  NH.CHjO.SOH  group.  This  latter  is  a  very  important  point,  for  an  NHj 
group  very  readily  attaches  to  it  other  complicated  groups,  whereas  the  ONa  groups 
are  rather  stable.  The  fact  that  one  of  the  NHj  groups  in  "  914"  is  already 
attached  to  a  complicated  group,  destroys  its  usefulness.  We  are,  therefore,  led 
to  the  conclusion  that  the  most  important  factor  in  these  two  compounds  is  the 
NHj  group.  Further  evidence,  in  support  of  this  conclusion,  is  given  by  the  action 
of  arsenophenylglycine,  which  will  be  referred  to  later.  In  this  compound  there  are 
two  NH.CHj.COOH  groups,  and  the  therapeutic  action  of  the  compound  compares 
unfavourably  with  that  of  "  600  "  and  of  "  914." 

It  must  not  be  forgotten  that  both  of  these  compounds  were  prepared  as 
reagents  against  the  Spirochaeta  jxtUida,  which  is  the  most  basophilic  phase  o'f  the 
life-cycle  of  the  Leucocytozoon  sijfhilidis.  In  future  research  it  would  be  well  to 
seek  for  a  compound  which  would  also  attack  the  most  acidophilic  phase  of  the 
leucocytozoon. 

Earlier  Arsenical  Compounds. 

Before  salvarsan  came  into  use,  three  other  ring  carbon  compounds  of  arsenic 
were  widely  used. 


CHEMOTHERAPY   AND   ITS   MODE    OF   ACTION   IN    SYPHILIS.  281 

(1)  Atoxyl,  or  monosodiumparaminopbenylarsenate.     The  composition  of  this 
body  is  shown  in  the  formula — 

NH., 


0 


O  =  iSs  —  ONa 

I 
OH 

Compare  this  formula  with  that  of  salvarsan,  and  it  will  be  seen  that  there 
are  several  points  of  difference  : — 

«.  The  compound  contains  only  one  benzene  ring  instead  of  two. 

/3.  The  arsenic  is  pentavalent  instead  of  trivalent. 

J.  The  OH  sroup  is  attached  to  the  arsenic  atom,  and  not  to  the   benzene 

ring. 
S.  The  arsenic  is  in  the  para  position  to  the  NHo  group,  and  not  in  the  meta 

position. 

This  body  is  amphoteric,  for  the  OH  group  is  acidic,  and  the  ONa  and  NHj 
groups  are  basic. 

Atoxyl  is  unstable,  and  it  exerts  a  highly  toxic  action  on  the  optic  nerve,  hence 
it  was  rapidly  superseded  by — 

(2)  Arsacetin,  which  is  the  acetyl  compound  of  the  above  body.     The  formula 
of  arsacetin  is  : — 

CH3.C0.HN 


O  =  As  —  ONa 

I 
OH 

This  body  is  less  toxic  and  more  stable  than  atoxyl.  The  addition  of  an  acetyl 
group  (CH;.CO)  is  a  common  device  in  chemistry,  when  one  desires  to  render  a  body 
more  stable. 

Both  of  these  bodies  are  much  more  toxic  than  salvarsan,  and  they  are  so 
because  the  arsenic  is  pentavalent.  The  fact  that  the  acetyl  compound  is  the  less 
toxic,  leads  to  the  conclusion  that  the  arsenic  does  not  exert  its  full  toxic  action 
until  the  compound  is  broken  down.  Now,  in  order  that  any  compound  may 
exert   an   action    on    the   syphilitic    organism,  the   compound   must   break   down, 


282  THE    BIOLOGY.    CLINICAL   ASPECT   AND   TREATMENT    OF   SYPHILIS. 

therefore  we  must  conclude  that  arsenic  should  be  trivalent  in  these  therapeutic 
agents.     This  brings  us  to — 

(3)  Aisenophenylglycine,  which  has  the  formula  : — 

As  =  As 

0     0 

HOOC.CH2.HN  NH.OH2COOH 

Let  us  note  the  characteristic  points  of  this  compound. 
".  It  has  two  benzene  rings. 
/3.  The  arsenic  is  trivalent. 
7.   It  is  a  substitution  product  of  acetic  acid. 
0.  The  arsenic  is  in  the  para  position  to  the  nitrogen. 
£  It  contains  two  acidic  hydrogen  atoms,  the  hydrogen  atoms  in  the  carboxyl 

(COOH)  groups. 
^.   It  contains  two  basic  hydrogen  atoms,  the  hydrogen  atoms  attached  to  the 

nitrogen  atoms. 

From  the  last  two  points  it  follows  that  the  body  is  amphoteric,  but  the  basic 
nature  of  the  body  is  very  feeble,  for,  not  only  is  one  basic  hydrogen  of  each  NH3 
group  substituted,  but  also  a  carboxyl  acidic  group  is  attached  to  the  substitution 
body. 

The  advantages  which  this  body  possesses  over  atoxyl  are,  that  the  arsenic  is 
trivalent,  and  that  there  are  two  benzene  rings. 

The  disadvantage  is,  that  the  basic  nature  of  the  body  is,  so  to  speak,  destroyed 
by  the  two  carboxyl  groups.  It  is,  of  course,  possible  that  the  acetic  acid  group 
is  broken  off  in  the  blood  stream,  for  the  blood  is  faintly  alkaline.  This  would 
leave  a  basic  NHj  group,  and  the  arsenic  compound  would  cease  to  be  amphoteric 
and  would  be  basic  only.  Judging  the  action  of  these  drugs  by  clinical  methods, 
it  would  appear  that  the  action  is  regulated  by  the  constitutional  formula  of  the 
drug  before  it  is  injected,  and  that,  however  near  to  the  base  a  salt  may  be  /!on- 
verted  by  the  serum,  its  action  is  never  so  powerful  as  when  a  similar  compound 
to  the  converted  product  is  itself  injected. 

French  Arsenical  Compounds. 

Several  other  arsenic  comiiounds  have  been  synthesised,  since  salvarsan  and 
neo-salvarsan  have  come  into  wide  use.  Mouneyrat  has  prepared  two  such  bodies 
— "  galyl  "  and  "  ludyl  " — and  he  considers  that  they  have  some  advantages  over 
the  earlier  preparations. 


CHEMOTHERAPY    AND    ITS   MODE    OF   ACTION   IN    SYPHILIS.  283 

Galyl  is  the  commercial   name  for  tetroxytetraminotetraphenyldiphosphoric 
acid,  and  its  constitutional  formula  is  : — 

(iH 

I 

PO 
HO        /^'\^    OH 

r^NH      HiNff^ 


NH      Hn'v/ 

HO  --  -^  -^      OH 

PO 

I 
OH 

The  chief  characteristics  of  this  body  are  that  it  contains  six  acidic  OH  groups 
and  four  trivalent  arsenic  atoms.  The  four  amino  (NH)  groups  are  linked  up  with 
acidic  phospho  groups,  and  so  they  have  lost  their  basic  nature. 

The  three  elements — arsenic,  phosphorus,  and  nitrogen — are  closely  related 
in  chemical  characteristics.  One  would,  therefore,  naturally  expect  that  the 
introduction  of  phosphorus  would  increase  the  activity  of  compounds  such  as  we 
are  considering.  It  must,  however,  be  noted  that  the  phosphorus  here  introduced 
is  in  an  acidic  group,  and  so  is  in  no  way  comparable  with  the  arsenic  or  nitrogen. 
Galyl  is  dissolved  in  sodium  carbonate  solution  before  injection,  and  so  it  is  rendered 
basic.  This  destruction  of  any  possible  amphoterism  must  of  necessity  militate 
against  its  usefulness.  I  have,  unfortunately,  no  clinical  experience  of  this  drug, 
but  if  some  accounts  are  correct,  that  it  is  as  potent  as  salvarsan,  it  would  be  a  point 
in  favour  of  the  importance  of  the  OH  groups.  This  drug  shows  still  further  that 
the  arsenic  is  not  the  most  important  group  in  the  compound,  since  it  contains 
35'3  per  cent,  arsenic. 

Ehrlich's  Conception  of  Chemotherapy. 

Having  given  a  brief  outline  of  the  chemistry  of  the  arsenic  compounds,  and 
of  their  mode  of  action,  as  it  might  be  deduced  from  a  comparison  of  their 
chemical  formulae,  Ehrlich's  own  views  on  their  action  must  now  be  given.'  ^  oiou 
Ehrlich's  work  is  based  upon  the  principle  that  there  are,  in  the  protoplasm 
of  the  parasites,  certain  chemical  groups  which  are  capable  of  combining  with 
certain  chemical  groups  of  the  drug  injected.  The  name  given  to  this  affinity  is 
"  chemoceptor.  " 


284  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT    OF    SYPHILIS. 

The  observation  was  also  made  that  parasites  co\ild  be  rendered  immune  to 
drugs.  Ehrlich  found,  as  a  result  of  experimentation,  that  trypanosomes,  for 
instance,  could  be  rendered  arsenic-fast.  Organisms  which  have  been  rendered 
arsenic-fast  are  immune  to  arsenic  compounds  only,  but  to  this  rule  there  is  one 
exception.  This  exception  requires  special  mention,  as  it  largely  influences  the 
theory  of  the  mode  of  action  of  these  arsenical  compounds. 

Ehrlich  found  that  certain  dyes,  such  as  pjTonin,  for  instance,  were  closely 
related  to  the  arsenoceptor,  since  parasites  which  had  been  rendered  immune  to 
pyronin  were  also  immune  to  the  arsenical  compounds. 

So  far  as  the  arsenical  compounds  were  concerned,  Ehrlich  was  primarily  of  the 
opinion,  that  the  sole  receptors  between  the  chemical  groups  in  the  protoplasm  of 
the  parasites  and  the  drugs  used  were  the  arsenic  receptors. 

That  other  receptors  existed,  as  well,  was  shown  only  when  it  was  noted  that 
the  action  of  arsenophenylglycine  was  not  affected  by  previously  working  on  the 
parasites  with  an  arsenic  derivative  of  phenyloxyacetic  acid  and  the  corresponding 
thio-compound.     The  chemical  formula  of  the  arsenic  compound  used  was — 

As  =  As 

/\ 

\J 

S 

I 

I 
CO2COOH 

hence  it  was  assumed  that  acetic  acid  receptors  existed  as  well. 

As  acetic  acid  receptors  were  said  to  exi.st  in  the  protoplasm  of  the  parasites, 
it  was  only  logical  to  suppose  that  amino-acid  receptors  would  be  found  there  also. 
Working  upon  this  hj'pothesis,  Ehi'lich  discovered  salvarsan.  According  to  Ehrhch, 
salvarsan  works  by  means  of  its  arsenic  receptors  and  its  orthoaniinophenol 
receptors. 

When  it  was  discovered  that  a  certain  drug  had  a  fatal  action  on  one  kind  of 
parasite  and  not  upon  another  Idnd,  although  in  both  instances  a  combination 
occurred  between  the  drug  and  the  bodies  of  the  parasites,  some  further  elaboration 
of  the  action  of  salvarsan  was  required. 

Consequently,  salvarsan  was  stated  to  act  in  the  following  way  : — The  arsenic 
was  considered  to  be  the  toxophore  group,  the  benzol  ring  the  carrier,  and  the 
amino  atoms  the  haptophore  group. 

Smnming  up  Ehrhch's  %dews  as  to  the  mode  of  action  of  salvarsan,  all  that 
can  be  really  said  is,  that  a  union  takes  place  between  the  drug  and  the  parasite. 


CHEMOTHERAPY    AND    ITS    MODE    OF   ACTION    IN    SYPHILIS.  285 

with  a  destructive  action  upon  the  latter.     What  the  nature  of  the  union  is,  and 
why  the  death  of  the  parasite  should  follow,  are  not  explained. 

It  must  not  be  forgotten  that,  so  far  as  syphiUs  was  concerned,  Ehrlich  was 
under  the  imprsssion  that  the  Spiroclmeta  ■pallida  was  the  cause,  and  that  the 
destruction  of  this  organism  would  result  in  the  cme  of  the  disease.  Moreover, 
most  of  the  experunents  were  conducted  in  vitro,  and  no  parallel  exists  between 
the  mode  of  action  of  a  certain  drug  in  vitro  with  its  mode  of  action  in  corpore. 

A  FuETHEK  Elaboration  of  My  Own  Views  upon  the  Action  of  Salvarsan. 

From  the  knowledge  now  to  hand  upon  the  cause  of  syphilis,^  -^  *  coupled  with 
the  work  I  have  done  upon  the  chemistry  of  the  organism  and  the  rationale  of  the 
Wassermann  reaction,*  I  will  attempt  to  explain  what  the  probable  action  of 
salvarsan  is,  and  upon  what  lines  chemotherapy  would  afiord  the  best  results  in  the 
future. 

Before  discussing  the  probable  mode  of  action  of  the  anti-syphilitic  drugs,  it 
would  be  best  to  pay  some  attention  to  the  way  the  body  naturally  protects  itself 
against  the  disease. 

The  cell  which  the  host  elaborates,  to  protect  itself  from  the  syphilitic 
organism,  is  the  plasma  cell.  This  cell  is  also  called  forth  in  any  chronic  inflamma- 
tion. In  all  instances,  the  plasma  cell  is  morphologically  the  same,  but  although 
its  gross  action  may  be  similar  in  every  instance,  it  is,  nevertheless,  specific  in 
each  case.  To  be  more  exact,  one  should  call  the  specificity  a  group  specificity, 
not  an  individual  specificity,  since  the  plasma  cells  behave  in  the  same  manner,  as 
here  described,  in  trypanosomiasis  as  in  syphihs. 

Take,  for  example,  three  plasmomata,  one  caused  by  syphilis,  another  by 
tuberculosis,  and  the  third  by  a  foreign  body.  If  an  injection  of  salvarsan  be  given 
to  patients  suffering  from  these  three  conditions,  and  sections  be  then  made  of 
all  three  lesions  again,  on  examination  it  will  be  found  that  only  the  plasma 
cells  in  the  case  of  syphilis  have  altered. 

To  explain  this  specificity,  we  must  probe  the  chemistry  and  physico-chemistry 
of  the  plasma  cell. 

This  may  be  best  done  by  referring  to  the  oxygen  positions  in  the  cells  as  a 
chain,  "  the  oxygen  chain."  Each  link  of  this  chain  will  be  made  up  of  free  oxygen 
and  a  ferment,  which  activates  it  in  varying  degrees,  according  as  to  whether  the 
first  or  last  link  of  the  chain  is  being  dealt  with.  The  first  fink  is  the  red  blood 
corpuscle,  which  contains  free  oxygen  and  a  peroxydase  :  the  ferment  action  is 
further  increased  by  the  iron  in  the  haemoglobin. 


286  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

Oxidising  enzymes  have  their  action  increased  by  metals  ;  attention  need 
only  be  drawn  to  the  extraordinary  accelerating  action  manganese  has  upon  some 
plant  oxydases,  in  support  of  this  statement. 

Eed  blood  corpuscles  supply  every  tissue  with  oxygen  in  an  active  state. 

The  next  link  in  the  chain  is  a  ma.st  cell,  one  of  the  functions  of  which  is  to 
supply  the  basal  cell  layer  of  the  epidermis  with  the  active  oxygen  for  the  tyrosine- 
tyrosinase  reaction,  which  results  in  the  production  of  pigment,  and  this  is  one  of 
the  protective  mechanisms  of  the  body. 

In  support  of  this  statement,  reference  need  only  be  made  to  the  well  recognised 
increase  of  mast  cells  in  Urticaria  pigmentosa,  ephelides,  and  all  known  pigmentary 
affections  of  the  sldn.  Another  function  is,  possibly,  to  supply  the  next  hnk  with 
free  active  oxygen,  namely,  the  nuclei  of  the  cells  of  inflammation. 

The  accelerating  element  in  the  mast  cell  is  possibly  sulphiu-.  The  next  link 
in  the  chain  is  an  eosinophile  cell,  the  action  of  which  is  probably  analogous  to  that 
of  the  mast  cell.  Between  these  two  cells  there  is  a  fundamental  difference,  which 
is  a  difference  of  reaction.  The  mast  cell  granules  are  basophilic,  the  eosinophile 
granules  are  acidophihc.  In  some  chronic  infections,  the  mast  cell  predominates ; 
in  others,  the  eosinophile  cell  is  most  to  the  fore  ;  both  are  carriers  of  oxygen 
ferments,  hence  the  reaction  of  the  base,  as  to  whether  it  is  acid  or  alkaline,  as  I 
have  already  suggested,  must  play  an  important  role  in  the  combating  of  infections. 

Nuclei  contain  free  oxygen  and  a  ferment  for  activating  the  same,  but  this 
ferment  is  not  nearly  so  strong  as  the  peroxydase  in  the  first  tliree  Hnks. 

Iron  is  the  accelerator  of  the  enzyme  action  in  the  nuclear  link,  and  possibly 
phosphorus  as  well.  The  oxygen  in  the  nucleus  is  used  by  the  protoplasm  of  the 
cell  and  of  the  nucleolus. 

The  last  link  in  the  chain  is  the  protoplasmic,  which  contains  oxygen,  but  no 
peroxydase.  The  activator  probably  comes  directly  from  the  nucleus,  and  indirectly 
from  other  cells  which  contain  peroxydases,  through  the  blood  serum. 

The  accelerator  of  the  enzyme  action  is  the  element  contained  in  the  drug 
which  is  prescribed  against  the  infection  ;  in  the  case  of  syphilis,  arsenic,  antimony, 
and  mercury,  for  instance.  The  lesions  of  syphiUs  may  vanish  without  treatment, 
because  of  the  ferment  action  of  the  serum,  and  of  the  protoplasm  of  the  plasma 
cells. 

The  protoplasm  of  plasma  cells  is  rich  in  lipoid-globuUn,  and  it  is  well  known 
that  lipoids  are  carriers  of  ferments  ;  therefore,  in  the  protoplasm  of  plasma  cells, 
and  in  the  serum,  the  host  has  the  means  of  overcoming  the  parasite.  Treatment 
assists  the  host's  resistance,  by  accelerating  the  ferments,  and  therefore  treatment 
destroys  the  parasites  indirectly.      I  have  shown  in  Chapters  X  and  XL VI  that 


CHEMOTHERAPY    AND    ITS    MODE    OF   ACTION   IN    SYPHILIS.  287 

the  lipoid-globulin  circulating  in  the  serum  and  in  the  plasma  cells  is  the  same. 
It  constitutes  the  antibody,  and  its  specificity  lies  in  its  stereo-chemical  molecular 
configuration.  The  action  of  antibody  is  one  of  adsorption,  a  phenomenon  which 
can  only  take  place  in  the  presence  of  a  ferment.  The  ferment  is  an  oxydase,  and 
is  what  we  commonly  call  complement.  Therefore  treatment  stimulates  the  com- 
plementary action  of  the  antibody,  and  it  also,  as  I  have  recently  discovered, 
increases  the  production  of  antibody.  It  is  the  antibody  which  destroys  the  parasite, 
the  ferment  is  only  the  activator  of  its  action,  which  is  one  of  adsorption  ;  con- 
sequently the  ferment  is  not  specific.  When  I  first  worked  at  this  subject,  and 
after  I  had  learnt,  from  my  investigations  into  the  chemistry  of  the  Leucocytozoon 
syphilidis,  that  the  parasite  was  made  up  of  a  lecithin-globulin  envelope,  which 
encased  nuclein,  and  before  I  had  discovered  the  modus  operandi  of  the  Wasser- 
mann  reaction,  which  gave  me  the  clue  to  the  whole  problem,  I  thought  that  the 
ferment  itself  was  specific,  and  I  therefore  attempted  to  find  a  specific  lecithase  and 
a  specific  protease.  Failing  in  my  attempts,  and  with  the  additional  knowledge 
that  I  had  gained  in  the  meantime,  I  came  to  consider  that  the  ferment  was  an 
oxydase.   In  support  of  this  view,  I  have  been  able  to  collate  the  following  facts  : — 

1.  The  granules  in  the  epithehal  cells  of  the  choroid  plexus  give  marked 
oxydase  reactions,  and,  as  shown  by  Pighini,®  they  are  able  to  synthesise  indo- 
phenol  from  a  mixture  of  a-uaphthol  and  dimethylphenylenediamine  hydrochloride, 
the  blue  colour  resulting  being  dependent  upon  an  oxydase  zymotic  action. 

2.  These  granules  are  increased  in  cases  of  degenerative  encephalitis,  which 
shows  that  the  zymotic  action  is  increased. 

3.  The  cerebro-spinal  fluid  obtains  its  active  properties  from  the  cells  of  the 
choroid  plexus. 

4.  I  have  been  able  to  prove  that  the  cerebro-spinal  fluid  from  cases  of 
degenerative  encephalitis  is  rich  in  oxydase  ferments  (amino-acidases),  while  normal 
cerebro-spinal  fluid  contains  none. 

5.  The  cerebro-spinal  fluid  from  cases  of  degenerative  encephalitis  and  meningo- 
encephalo-myelitis  gives  the  goldsol  reaction,  a  reaction  which  is  dependent  upon 
the  presence  of  an  oxydase. 

6.  The  cerebro-spinal  fluid  in  cases  of  syphilis  of  the  central  nervous  system 
contains  an  excess  of  globulin. 

7.  This  globulin  is  in  an  adsorption  complex  with  lipoids. 

8.  Oxydases  are  frequently  carried  by  lipoids  ;  therefore,  not  only  is  there 
proof  that  the  cerebro-spinal  fluid  from  cases  of  syphilis  of  the  central  nervous 
system  contains  oxydase  ferments,  but  also  that  the  ferments  are  carried  by  the 
lipoid-protein  complexes,  the  adsorptive  action  of  which  they  accelerate. 

T 


288  THE   BIOLOGY,    CLINICAL  ASPECT   AND   TREATMENT   OF   SYPHILIS. 

This  view  is  still  further  supported  by  the  analogy  to  the  blood  serum  and 
plasma  cells. 

Still  more  convincing  is  the  fact,  that  I  have  been  able  to  prove  that  the 
granules  of  the  epithehal  cells  of  the  choroid  plexus,  and  the  tigroid  or  Nissl's 
granules  to  be  found  in  the  nerve  cells,  consist  of  a  lipoid-protein,  and  behave  to 
reagents  similarly  to  the  envelope  of  nucleoli,  the  protoplasm  of  plasma  cells, 
and  the  envelope  of  the  syphilitic  organism. 

Pighini  showed  that  Nissl's  granules  also  sjmthesised  indophenol,  especially 
those  around  the  nucleus,  which  was  to  be  expected,  since  the  nucleus  contains  free 
oxygen  and  an  oxidising  ferment. 

The  explanation  of  the  protective  mechanism  of  the  serum  and  the  cerebro- 
spinal fluid,  against  the  syphilitic  parasite,  by  means  of  adsorption,  a  process  which 
is  dependent  upon  oxidising  ferments,  is  simple  ;  in  fact,  it  is  its  smiplicity  which 
makes  one  think  that  it  is  correct,  for  the  more  one  considers  how  the  body  protects 
itself,  the  more  convinced  one  becomes  that  it  is  not  nearly  so  elaborate  a  process 
as  all  have  been  led  to  believe. 

After  all,  why  should  such  an  exceedingly  complex  ferment  as  a  lecithase  or 
protease  be  manufactured  specifically  against  syphilis  ?  Supposing  another 
protozoal  disease  sprang  up  in  our  midst  to-morrow,  the  body  would  be  ready  to 
protect  itself,  and  it  could  not  possibly,  in  the  short  time  at  its  disposal,  manufacture 
highly  complex  specific  ferments.  The  actual  process  of  destruction  of  the  organism 
probably  takes  place  in  the  following  manner  : — The  host  elaborates  lymphocytes, 
these  in  turn  give  rise  to  plasma  cells,  from  the  protoplasm  of  which  an  oxydase 
lipoid-globulin  is  freed  into  the  serum.  This  oxydase  lipoid-globulin  has  a 
stereo-chemical  molecular  configuration  homologous  to  that  of  the  sypliihtic 
parasite,  consequently  adsorption  between  the  two  takes  place,  when  they  come 
in  contact.  Adsorption  results  in  precipitation,  and  finally  hydrolysis,  hence 
both  the  lipoid-globulin  molecules  of  the  parasite  and  of  the  serum  become  broken 
up.  As  to  whether  further  sjmiptoms  of  the  disease  will  become  manifest,  that  will 
depend  upon  whether  the  host  can  manufacture  more  hpoid-globuhn,  befo're  the 
spore  can  develop  and  form  new  male  and  female  bodies. 

A  most  interesting  point  now  crops  up,  namely,  why  are  the  spirochaetae 
destroyed  more  quickly  than  the  other  phases,  and  why  so  quickly  by  salvarsan  ? 

Chemistry  showed  that  the  male  gamete,  or  Spirochaeta  pallida,  had  the 
strongest  reducing  action  of  all  the  phases.  In  in  vivo  staining,  it  showed  a  marked 
affinity  for  methylene  red,  and  it  increased  the  reducing  action  of  the  female  cell 
after  impregnation. 

In  this  reducing  action,  in  my  view,  lies  the  solution  of  the  problem  as  to  why 


CHEMOTHERAPY   AND   ITS   MODE    OF   ACTION    IN    SYPHILIS.  289 

the  male  cell,  and  not  the  other  cells,  stains  with  silver  nitrate  in  Levaditi's  method 
of  staining,  and  as  to  why  the  action  of  salvarsan  is  more  marked  upon  the  male 
cell. 

The  reducing  action  is  due  to  an  unsaturated  fatty  acid — a  substance  in  which 
the  male  cell  is  especially  rich,  for  two  reasons  :  (a)  because  it  is  the  result  of  an 
intracellidar  development ;  (6)  because  it  has  a  very  important  function  to  perform, 
namely,  that  of  impregnation.  In  other  phases  where  the  metabolism  is  less  active, 
and  the  cells  are  more  or  less  in  resting  forms,  the  fatty  acids  are  more  hkely  to  be 
saturated  than  unsaturated. 

The  more  unsaturated  a  fatty  acid  is,  in  a  complex,  the  more  free  OH  or 
hydroxyl  groups  will  there  be. 

To  these  free  OH  groups,  different  chemical  substances  can  become  attached  ; 
therefore,  the  Spirochaeta  pallida,  owing  to  the  fact  that  it  contains  more  free  OH 
groups,  can  have  its  lipoid  envelope  altered  by  substances  which  combine  immediately 
with  it. 

In  staining  tissue  with  silver  nitrate,  in  order  to  get  a  black  colour,  two  things 
are  necessary  :  one  is  that  the  silver  must  be  taken  up  ;  the  other  is  that  it  must 
be  reduced  in  situ.  Owing  to  the  free  OH  groups  in  the  lipoid  envelope  of  the 
Spirochaeta  pallida,  the  silver  is  readily  taken  up,  and  is  reduced  by  the  pyrogallic 
acid.  In  the  other  phases,  on  the  other  hand,  there  are  no  free  OH  groups  to  take 
up  the  silver,  so  they  therefore  cannot  stain  black.  The  action  of  salvarsan  is  also 
probably  to  be  explained  in  this  way. 

The  "  606  "  molecule  fixes  on  to  the  free  OH  groups,  with  the  result  that  the 
arsenic  immediately  robs  the  colloidal  membrane  of  oxygen,  hence  the  death  of  the 
organism.  As  there  are  no  free  OH  groups  in  the  other  phases,  salvarsan  caimot 
become  so  readily  attached  to  them.  The  destruction  of  the  other  phases  is  brought 
about  partly  by  the  direct  action  of  salvarsan,  and  partly  by  the  adsorptive  action 
of  the  protoplasm  of  plasma  cells,  and  the  lipoid-globulin  (antibody)  of  the  serum, 
which  action  the  salvarsan  stimulates  and  accelerates.  Therefore,  the  action  of 
salvarsan  upon  the  spirochaetae  is  wholly  a  direct  one,  and  upon  the  other  phases 
partly  an  indirect  one. 

From  the  little  that  has  already  been  said,  it  will  be  at  once  understood  why 
sjrphihs  is  so  hard  to  cure,  for  the  simple  reason  that  the  spore  contains  little  or  no 
lecithin-globulin,  and  therefore,  as  a  spore,  it  is  only  potentially  harmful,  and  so  is 
not  touched  immediately  by  the  host's  antibodies,  or  by  the  direct  action  of  salvarsan. 

If  the  spore  cannot  be  vanquished  before  it  has  entered  what  may  be  called  its 
resting  stage,  all  that  we  can  hope  to  do  is  to  prevent  its  re-developing.  This  we 
do  by  following  up  salvarsan  with  mercury. 

t2 


290  THE    BIOLOGY,    CLINICAL   ASPECT    AND    TREATMENT   OF   SYPHILIS. 

The  question  might  now  very  naturally  be  asked,  if  the  action  of  salvarsan  is 
an  indirect  one,  why  arsenic  should  be  more  active  than  mercury,  since,  under 
ordinary  circumstances,  the  latter  is  a  more  powerful  anti-syphihtic  remedy. 

In  my  opinion,  both  mercury  and  arsenic  act  as  catalysts,  i.e.,  that  they  accelerate 
a  reaction  going  on  spontaneously,  but  more  slowly  without  their  assistance. 

A  ratio  exists  between  the  intensity  of  action  of  a  catalyser  and  the  degree  of 
the  colloid  state  in  which  the  catalyser  is.  In  salvarsan,  the  arsenic  is  in  a  colloidal 
state,  hence  its  action  would  necessarily  be  greater  than  that  of  any  mercurial  com- 
pound which  we  are  in  the  habit  of  using.  The  proof  of  what  has  been  said  can 
be  found,  if  we  compare  the  action  that  different  manganese  compounds  have  on 
plant  oxydases.  Manganese  formate,  for  instance,  has  nothing  like  such  a  powerful 
accelerating  action  upon  plant  oxydases  as  colloidal  manganese  hydroxide.  The 
latter  is  colloidal,  and  the  former  is  not. 

In  many  other  synthetic  organic  arsenical  compounds,  the  arsenic  is  also  in  a 
colloidal  state,  but  the  action  of  the  drug  is  very  inferior  to  that  of  salvarsan. 
Therefore  this  fact  at  once  suggests  that  salvarsan  when  injected  becomes  fixed  to 
the  substance  which  the  arsenic  is  going  to  accelerate. 

The  proof  that  this  is  not  pure  theory  is  seen  in  the  following  statements  : 
I  showed  in  my  work  on  the  Wassermann  reaction  that  complement  and  antibody 
were  the  same  substance  in  one,  and  that  they  constituted  the  lipoid-globulin  or  the 
protective  substance  of  the  serum.  Further,  that  the  action  of  antibody  was  to 
adsorb  its  antigen,  which  it  did  by  means  of  its  ferment  properties  which  constitute 
the  complement,  and  that  adsorption  resulted  in  precipitation  and  final  hydrolysis 
of  the  bodies  adsorbed.  Further,  that  the  action  of  "  606  "  is  to  break  down  the 
lipoid-globulin  of  the  serum  and  that  of  the  plasma  cells.  Again,  that  adsorption 
takes  place  between  the  amino  and  fatty-acid  groups. 

Now,  salvarsan  has  amino-acid  groups  and  OH  groups  which  other  organic 
arsenical  compounds  have  not,  hence  sufficient  proofs  can  be  brought  forward  to 
allow  the  assumption  to  be  made,  that  salvarsan  fixes  on  to  the  lipoid-globulin  of 
a  syphilitic  serum,  of  the  plasma  cells  in  a  case  of  syphilis,  and  of  the  syphilitic 
parasites  by  nature  of  its  amino  and  OH  groups,  hence  allowing  the  arsenic  free 
play  as  a  catalyst.  Since  the  "  606  "  molecule  enters  into  adsorption  with  the 
lipoid-globulin  of  a  s}qDhilitic  serum,  and  of  the  plasma  cells  in  a  case  of  syphilis,  it 
will  be  seen  that  Ehrlich's  statement  that  the  drug  is  parasito-tropic  only  and  not 
organo-tropic,  cannot  hold  good.  For  a  drug  to  be  parasito-tropic  it  must  be  organo- 
tropic. 

There  can  also  be  no  doubt  that  amphoterism  plays  a  very  great  part  in  the  way 
in  which  salvarsan  acts.     I  have  already  suggested  that  its  action  is  greatest  on  the 


CHEMOTHERAPY   AND   ITS    MODE    OF   ACTION   IN    SYPHILIS.  291 

spirochaetal  phase,  be3ause  the  spirochaeta  is  the  most  basophilic  of  all  the  phases, 
owing  to  the  fact  that  it  contains  an  unsaturated  fatty-acid  group,  hence  it  would 
be  expected  that  the  action  of  "  606  "  was  more  marked  in  the  late  stages  of  syphilis 
than  in  the  earl_v  ones.  This  happens  to  be  the  case,  since  the  lipoid-globulin  of  the 
serum  is  more  readily  broken  down  by  "  606  "  in  the  case  of  a  late  recurrent 
syphilide  than  in  the  case  of  generalised  syphilis.  I  have  shown  in  Chapter  X. 
that  serum  from  a  late  case  of  syphilis  is  richer  in  COOH  groups  than  that  from  a 
case  of  early  syphilis. 

A?  the  former  serum  is  more  readily  broken  down  by  salvarsan,  and  as  the 
spirochaetal  phase  is  the  phase  most  easily  destroyed,  it  is  reasonable  to  assume 
that  there  is  a  ready  attachment  between  salvarsan  and  the  COOH  groups  of  the 
bodies  aforementioned. 

Amino  groups  can  be  fixed  by  COOH  groups,  therefore  one  cannot  say  for 
certain,  whether  the  attachment  just  mentioned  is  dependent  more  upon  the  OH 
groups,  or  upon  the  NH^  groups  of  the  "606."  Further  research  must  gauge  the 
imporbance  of  the  OH  groups.  Suffice  it  to  say  at  present,  that  the  NH^  groups 
are  probably  the  most  important  in  the  salvarsan  molecule.  That  this  is  true  is 
seen  by  the  fact,  that  any  alteration  in  the  NH^  groups  diminishes  the  efficiency  of 
the  drug.  Hence  the  reason  why  neo-salvarsan  is  not  so  potent  as  salvarsan ;  in 
spite  of  the  fact  that  it  contains  two  hydroxyl  groups,  which  are  less  stable  than 
the  ONa  groups  in  salvarsan. 

In  Ehrlich's  own  work  there  appear  to  me  to  be  two  points  which  require 
very  careful  consideration.  One  is  that  parasites  which  have  been  rendered  arsenic- 
fast  are  also  pyronin-fast,  and  the  other  is  that  although  salvarsan  may  be  linked 
on  to  a  parasite,  it  need  not  necessarily  prove  fatal  to  that  parasite.  If  there  is  a 
relationship  between  arsenical  immunity  and  pyronin  immunity  it  cannot  be  the 
arsenic  that  the  parasites  become  immune  to. 
If  the  formula  of  pyronin  is  studied — 

CI 

I 

() 
HoN/\^\/\NH., 


CM  2 

it  will  be  noticed  that  there  are  two  amino  groups.  Now  there  are  two  amino 
groups  in  salvarsan,  and  from  what  has  been  already  said  it  would  appear  to  be 
due  to  these  two  amino  groups  that  the  drug  becomes  attached  to  the  syphilitic 
parasites,  the  plasma  cells,  and  the  lipoid-globulin  of  a  syphilitic  serum. 


292  THE   BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   SYPHILIS. 

I  have  little  doubt  in  my  own  mind,  but  that  immunity  is  mainly  dependent 
upon  the  adsorption  between  certain  amino  groups,  and  the  case  in  point  certainly 
favours  such  a  view. 

In  view  of  the  fact  that  parasites  which  are  salvarsan-fast  are  also  pyronin- 
fast,  it  proves  that  immunity  is  not  acquired  against  the  arsenic,  therefore  the 
parasites  cannot  be  strictly  said  to  be  arsenic-fast.  So  far  as  future  experimental 
work  is  concerned,  it  is  a  very  important  fact  to  have  in  front  of  one,  namely,  that 
an  immunity  cannot  be  produced  against  a  catalyst.  The  fact  that  salvarsan  can 
become  attached  to  parasites,  and  yet  not  be  fatal  to  them,  is  an  observation  in 
which  there  is  a  great  deal  wrapped  up. 

During  the  time  when  I  was  working  at  the  rationale  of  the  Wassermann  reaction, 
I  thought  that  for  adsorption  to  take  place  between  two  molecules,  both  of  which 
possessed  amino  groups,  it  was  necessary  that  they  should  have  homologous  stereo- 
chemical molecular  configurations.  This  idea  soon  proved  to  be  ■wTong,  when 
fixation  occurred  of  a  non-specific  antigen,  and  of  an  antigen  whose  amino  groups 
had  been  converted  into  methane  groups  by  formalin,  respectively  with  the  serum 
globulin  from  a  case  of  svphilis. 

As  a  result  of  further  experiments,  I  proved  that  the  complement  fixation  test, 
as  applied  to  syphilis,  in  contradistinction  to  the  true  bacterial  complement  fixation 
tests,  depended  not  upon  the  molecules  having  homologous  stereo-chemical 
molecular  configurations,  but  solely  upon  their  number  and  size. 

Application  of  this  to  the  action  of  salvarsan,  confirms  the  points  just  mentioned. 
The  attachment  of  salvarsan  to  the  syphilitic  parasites,  to  the  plasma  cells,  and  to  the 
lipoid-globulin  in  a  case  of  syphilis,  cannot  possibly  be  due  to  an  homologous  stereo- 
chemical molecular  configuration  between  the  adsorbed  molecules,  since  for  one 
thing  alone,  salvarsan  is  an  optically  inactive  body. 

The  adsorptive  capacity  as  a  whole,  appears  to  be  greater  in  the  case  of  a 
syphilitic  serum  than  in  the  case  of  a  serum  from  any  bacterial  disease,  and  it  appears 
to  be  greater,  the  later  the  case  of  syphilis. 

As  the  lipoid-globulin  from  a  late  case  of  syphilis  is  richer  in  COOH  groups 
than  that  from  an  early  case  of  syphilis,  it  follows  that  any  substance  it  happens 
to  adsorb  will  tend  to  break  down  the  molecules.  The  first  result  of  breaking 
down  the  lipoid-molecules  is  to  increase  the  area  over  which  they  can  work,  hence 
the  probable  reason  why  late  syphilitic  lesions  disappear  more  quickly  under 
treatment  than  do  early  ones.  In  my  opinion,  in  the  case  of  syphilis,  and  in 
all  protozoal  diseases,  the  lipoid-globuhn  molecule  appears  to  be  bigger,  and  to 
have  a  greater  adsorptive  capacity  than  the  lipoid-globulin  molecules  in  the  serum 
of  bacteria]  diseases. 


CHEMOTHERAPY    AND    ITS   MODE    OF   ACTION   IN    SYPHILIS.  293 

The  bigger  the  size  of  the  molecule,  and  ths  greater  its  adsorptive  capacity,  the 
more  easily  will  a  di'ug  like  salvarsan  be  adsorbed,  and  the  more  readily  the  adsorbed 
compound  will  break  down.  WTien  the  lipoid-globulin  first  breaks  down,  the  area 
of  its  action  is  widened,  hence  the  catalytic  action  of  the  arsenic  will  have  its  fullest 
play.  If  salvarsan  became  attached  to  a  small  molecule,  the  adsorbed  compound 
would  not  break  down,  at  all  events,  not  until  much  later  than  it  does  in  the  case 
of  syphihs.  This  would  mean  that  the  arsenic  would  get  little  chance  of  acting  as 
a  catalyst.  Therefore,  salvarsan  seems  to  act  in  protozoal  diseases  because  of  the 
physical  state  of  the  lipoid-globulin  molecules  of  the  serimi,  and  it  fails  to  act  as  a 
bactericidal  agent,  because  the  lipoid-globulin  molecules  in  the  sermn  of  bacterial 
diseases  do  not  possess  the  requisite  physical  properties. 

Summary. 

Salvarsan  becomes  attached  to  the  lipoid-globuhn  molecules  of  the  s}'philitic 
parasite,  the  plasma  cells,  and  the  serum,  by  N^rtue  of  its  amino  groups  and  of  the 
peculiar  physical  properties  of  protozoal  lipoid-globulin.  It  attacks  those  phases 
of  the  Leucocytozoon  syphilidis  in  which  reaction  is  most  marked,  especially  the 
spirochaetal  phase,  in  virtue  of  its  free  hvdroxyl  groups. 

The  arsenic  acts  as  a  catalyst,  that  is  to  say,  it  accelerates  the  complementary 

or  oxydase  action  of  the  lipoid-globulin  (antibody)  of  the  serum,  which  destroys 

the  parasites  by  means  of  adsorption. 

1  McDonagh  (1913),  "  Proc.  Roy.  Soc.  Med."  (Path.  Sec),  vi,  83. 

"  McDonagh  (1913),  "  Demiat.  Woch.,"  Ivi,  413. 

^  McDonagh  and  Mackenzie  Wallis  (1913),  "  Biochem.  Journ.,"'  vii,  517. 

*  McDonagh  (1914),  "  Archiv.  f.  Derm.  u.  Syph.,"  cxix,  205. 

5  McDonagh  (1915),  "  The  Quart.  Journ.  of    Med.,"  viii.  129. 

8  Pighini  (1912),  "Biochem.  Zeitschr.,"   xlii,   124. 

'  Ehrlioh  u.  Bertheim  (1907),  "  Berichte  der  Deutsch.  Chem.  Gesellsch.,"  xl.  3292. 

8  Ehrhch  u.  Bertheim  (1908),  "  Berichte  der  Deutsch.  Chem.  Gesellsch.,"  xli,  931,  1672. 

9  Ehriich  u.  Bertheim  (1910),  "  Berichte  der  Deutsch.  Chem.  Gesellsch.,"  xliii,  924. 

1°  Ehrhch  u.   Hata  (1910),   "  Die  experimentelle  Chemotherapie  der  Spirillosen."      Springer. 

Berlin. 
"  Ehriich  u.  Gonder  (1913),  "  Handbuch  dor  pathog.  Mikroorganismen,"  iii,  337. 

\\'ORKS   CONSULTED. 
Ehrhch  (1912),  "  Zeitschr.  f.  Chemother.,"  i,  1. 
Moore,  Nierenstein  and  Todd  (1907),  '"  Biochem.  Journ.,"  ii,  300. 
Wolflf  (1908),  D.R.P.  213.394. 
Meister.  Lucius  u.  Briining,  D.R.P.  204664. 
Meister.  Lucius  u.  Briining,  D.R.P.  206057. 
Meister.  Lucius  u.  Briining,  U.S.  pat.  888321. 

References  (1908),  "Chem.  Soc.  Trans.,"  p.  93,  1180,  1893,  2144. 
References  (1909),  "  Chem.  Soc.  Trans.,"  p.  95,  1473. 


CHAPTER  XXVIII. 
TOXIC  SYMPTOMS  OF  SALVARSAN  AND  NEO-SALVARSAN. 

Before  opening  this  chapter,  the  reader  must  be  fully  aware  that  the 
salvarsan  used  when  the  drug  first  came  upon  the  market,  was  less  potent  and 
toxic  than  the  samples  used  for  experimental  purposes.  Before  the  profession  was 
able  to  obtain  salvarsan  there  were  two  varieties,  "  Ideal  "  and  "  Hyperideal." 
Both  of  these  were  less  soluble  than  salvarsan,  and,  although  they  were 
more  potent  and  more  toxic,  it  was  partly  on  account  of  the  insolubility  that 
salvarsan  superseded  the  "  Ideal  "  and  "  Hyperideal." 

As  we  all  know,  salvarsan  had  not  been  in  use  long  before  neo-salvarsan  saw 
daylight.  The  reason  which  prompted  the  discovery  of  neo-salvarsan  was  the 
desire  to  obtain  an  easily  soluble  and  neutral  salt,  since  some  of  the  unpleasant 
symptoms  following  the  use  of  salvarsan  were  undoubtedly  to  be  attributed  to  an 
excess  of  sodium  hydrate,  which  it  was  necessary  to  add  to  neutralise  the  solution, 
as  salvarsan  was  an  acid  salt.  Speaking  generally,  neo-salvarsan  is  not  quite  so 
potent  as  salvarsan. 

Relationship  Between  Toxicity  and  Potency. 

In  my  experience,  a  direct  ratio  exists  between  potency  and  toxicity,  that 
is  to  say,  that  the  more  potent  a  special  sample  of  salvarsan  is,  the  more  toxic  it 
is.     Clinically,  one  sees  this  in  many  instances. 

To  give  an  example.  Case  46. — A  patient,  a  woman  aged  36,  had  on  the  left  breast 
a  primary  sore  which  had  healed,  but,  when  she  came  up  for  examination,  she  'was 
covered  from  head  to  foot  with  a  large  papular  rash.  The  papules  were  of  the  dense 
form,  a  form  which,  under  ordinary  circumstances,  requires,  even  under  salvarsan, 
at  least  a  month  to  disappear,  often  more.  I  gave  the  patient  an  intravenous 
injection  of  neo-salvarsan  (0"45  grm.).  For  three  days  afterwards  the  patient  ran 
a  temperature  of  103°  F.,  felt  very  ill,  complained  of  pains  all  over,  and  was  sick. 
Five  days  later  I  gave  another  injection  of  neo-salvarsan  (0"45  grm.).  The  patient 
was  ill  for  nearly  a  week  afterwards,  and  the  symptoms  were  more  pronounced 
than  on  the  first  occasion.      Although  the  rash  began  to  fade  on  the  third  day  after 


TOXIC    SYMPTOMS    OF   SALVARSAN    AND    NEO-SALVARSAN.  295 

the  first  injection,  it  all  of  a  sudden  vanished  in  twenty-four  hours  on  the 
fourth  day  after  the  second  injection,  but  prior  to  its  disappearance,  the  patient 
developed,  on  the  second  day  after  the  second  injection,  a  diffuse  and  very  severe 
toxic  erythema.  Ten  days  later,  on  examining  the  patient,  it  would  have  been 
difficult  to  say  that  she  had  ever  had  a  syphilitic  eruption.  I  then  gave  a  third 
injection  of  neo-salvarsan  (0'45  grm.),  as  I  thought  the  symptoms  after  the  first 
two  were  probably  due  to  the  endotoxines  liberated  from  the  wholesale  destruction 
of  the  syphilitic  parasites.  The  patient  was  violently  sick  and  ill,  for  two  days,  the 
temperature  was  106°  F.,  and  she  again  developed  a  toxic  erythema.  Although  she 
was  able  to  get  up  on  the  fifth  day,  the  patient  felt  very  ill  and  weak  for  a  fortnight. 
The  future  course  was  uneventful.  The  water  used  in  this  case  was  pure,  and  other 
patients  were  injected  on  the  same  days,  without  showing  a  single  toxic  symptom. 

Before  the  water  question  was  shown  to  be  so  important,  I  had  two  cases  which 
developed  jaundice  after  the  second  injection  of  salvarsan.  One  patient  was  in 
the  early  generalisation  stage,  and  the  other  patient  had  a  recurrent  palmar 
syphilide.  These  patients  were  treated  in  February,  1911.  The  toxic  manifesta- 
tions were  sufficient  to  lay  them  both  up  for  nearly  three  months.  Neither  would 
consent  to  have  any  mercurial  treatment.  I  have  frequently  examined  them 
since,  and  have  recently  examined  their  blood  and  cerebro-spinal  fluid,  and  I  have 
also  given  them  a  provocative  injection  of  neo-salvarsan  (0'45  grm.),  all  with 
negative  results. 

I  have,  on  the  other  hand,  had  cases  in  which  severe  toxic  symptoms  do  not 
seem  to  have  had  such  a  beneficial  action  on  the  syphilitic  lesions.  Since  I  first 
began  to  use  salvarsan,  I  have  kept  a  book  in  which  I  have  noted  every  evil  effect 
from  its  use.  In  many  of  the  earlier  cases,  the  water  was,  no  doubt,  to  blame, 
because  for  the  last  two  years  and  more  I  have  not  seen  a  toxic  symptom  of  note. 

The  Water  Question. 

Unfortunately  there  is  no  drug  which  has  not,  at  some  time  or  other,  given 
rise  to  toxic  symptoms,  so  differently  constituted  is  each  human  frame.  Evolution 
up  the  animal  scale  increases  this  idiosyncrasy  towards  drugs,  the  human  body 
being  more  prone  to  toxic  symptoms,  and  behaving  more  inconsistently  towards 
drugs  than  those  of  the  lower  mammalia  ;  therefore,  useful  as  animal  experiments 
may  be,  the  results  cannot  be  taken  as  being  identical  with  those  obtained  in 
human  beings. 

Salvarsan,  used  in  curative  doses  on  animals,  is  absolutely  non-toxic  ;  so  it  is 
in  the  majority  of  human  beings,  but,  since  we  cannot  pick  out  beforehand  those 
individuals  to  whom  it  will  be  toxic,  it  is  well  to  bear  in  mind  the  toxic  symptoms 


296  THE    BIOLOGY,    CLIXICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

that  may  occur.  Patients  with  an  idiosyncrasy  for  arsenic,  which  is  often 
hereditary,  do  not  exhibit  this  idiosyncrasy  to  salvarsan,  and  it  is  extremely 
doubtful  whether  any  one  is  unduly  susceptible  to  this  drug. 

The  feeling  of  malaise,  as  that  is  all  that  the  toxic  symptoms  amount  to 
nowadays,  which  sets  in  after  the  first  two  injections  in  the  generalisation  stage, 
may  in  some  cases  be  due  to  the  action  of  the  drug  on  the  spirochaetae,  since,  in  a 
few  of  the  more  severe  cases,  the  reaction  is  greater,  and  this  is  especially  to  be 
noticed  when  malaria  complicates  syphilis. 

When  we  weve  less  carefid  in  the  preparation  of  the  distilled  water  which  we 
used,  toxic  symptoms  were  frequent.  Wechselmann^  was  the  first  to  point  this 
out,  and  he  showed  that  the  reaction  was  produced  by  the  dead  bodies  of  bacteria 
and  fungi  or  their  toxines,  which  cj[uickly  contaminate  distilled  water  that  has  been 
allowed  to  stand. 

Since  I  have  used  water  which  has  been  prepared  in  the  way  to  be  shortly 
mentioned,  my  patients  have  suffered  no  inconvenience  from  headache,  rigor, 
pyrexia,  or  sickness,  be  it  their  second  or  even  fifteenth  consecutive  injection. 

Further,  the  toxic  symptoms  which  we  have  learnt  to  associate  with  salvarsan 
can  be  produced  in  animals,  by  the  use  of  distilled  water  alone.  Dispensers  have 
always  had  trouble  with  distilled  water,  getting  precipitates  with  drugs  which 
should  not  precipitate.  Surgeons  have  also  realised  that  intravenous  injections 
of  saline  often  gave  rise  to  unpleasant  symptoms,  but  unfortunately  most  have  not 
had  the  opportunity  of  estimating  why,  owing  to  the  fact  that  saline  injections  are 
not  generally  used,  unless  the  patient  is  almost  moribund. 

Wechselmann's  discovery  is  of  immense  value,  as  it  renders  the  administration 
of  salvarsan  innocuous.  Like  most  people,  I  was  sceptical  when  I  read  that  the 
toxic  symptoms  following  salvarsan  were  due  to  the  distilled  water,  and  I  was 
convinced  only  after  personal  trial.  It  may  be  said  that  some  of  the  toxic  symptoms 
are  so  typical  of  arsenical  poisoning  that  they  cannot  be  due  to  the  water ;  but  may 
not  this  be  exj)lained  by  saying  that  the  tissues  have  primarily  been  damaged  by 
the  impure  distilled  water,  and  so  have  fallen  an  easy  prey  to  the  arsenic  ?  This'seems 
to  me  to  be  most  likely,  because  toxic  symptoms  due  to  the  distilled  water  set  in 
about  two  hours  after  the  injection,  while  those  due  to  arsenic  do  not  do  so  until 
the  third  day.  Moreover,  the  arsenic  ion  is  not  detached,  in  sufficient  quantities, 
soon  enough  to  give  rise  to  those  toxic  symptoms  which  set  in  immediately  after 
the  injection.  Again,  most  of  the  severe  cases  have  occurred  after  the  second 
injection,  when  the  immediate  efiects  of  the  first  one  were  pronounced.  These 
symptoms  set  in  within  a  few  hours  of  a  second  injection,  then  the  next  day  the 
patient  recovers,  to  get  signs  of  arsenical  poisoning  on  the  third  or  fourth  day. 


TOXIC    SYMPTOMS    OF   SALVARSAN    AND    NEO-SALVARSAN.  297 

None  of  these  toxic  symptoms  would,  in  my  opinion,  have  occurred,  had  I  used 
redistilled  distilled  water.  The  fact  that  a  patient  may  have  a  severe  reaction  after 
his  first  injection,  and  none  after  his  second,  clearly  shows  that  the  arsenic  plays 
no  part,  since  the  same  quantity  is  used  in  both  injections ;  it  can  therefore  be 
only  the  distilled  water  that  varies.  If  one  patient,  of  several  who  are  injected 
on  any  given  day,  has  a  severe  reaction,  all  the  rest  will  have  the  same  ;  while  if 
one  escapes,  all  escape.  On  more  than  one  occasion  I  have  given,  on  the  same  day, 
four  injections^two  with  redistilled  distilled  water  and  two  with  distilled  water 
forty-eight  hours  old,  the  tubes  of  salvarsan  all  coming  from  the  same  packet. 
The  former  two  had  no  reaction,  while  the  latter  were  sick,  had  rigors,  and  a  rise 
of  temperature. 

On  another  occasion,  I  used  half  doses  of  salvarsan  with  old  distilled  water, 
and  gave  full  doses  with  the  redistilled  distilled  water,  the  amount  of  fluid  being 
equal  in  all  (half  pint).  The  patients  who  had  the  half  dose  had  a  marked  reaction, 
while  those  who  had  the  full  dose  had  none. 

Evidence  is  therefore  complete  as  to  the  necessity  of  invariably  using  specially 
prepared  distilled  water,  which  is  best  made  as  follows  : — 

Ordinary  tap-water  is  used ;  there  is  no  advantage  in  using  redistilled  water. 
It  is  boiled  vigorously  in  a  hard  glass  vessel,  first  at  atmospheric  pressure,  then  at 
reduced  pressure,  so  as  to  ensure  complete  freedom  from  all  volatile  bodies.  The 
boiled  water  is  then  transferred  to  the  hard  glass  still,  which  has  been  carefully 
sterilised.  The  distillation  is  carried  out  under  a  pressure  of  3  to  3 '25  atmospheres, 
by  which  means  the  boiling  point  is  considerably  raised.  In  order  to  avoid  mechanical 
transference  of  any  contaminating  body,  the  heat  applied  must  be  so  regulated  that 
distillation  goes  on  slawly,  and  a  water-trap  should  be  interposed  between  the  still 
and  the  receiver.  Glass  taps  must  be  used  for  cutting  off  one  vessel  from  another, 
and  each  tap  must  be  carefully  ground  in  with  carborundum.  The  preparation  gains 
in  interest  from  the  fact  that  some  care  and  ingenuity  in  manipulation  is  required, 
for  high-pressure  steam  gives  an  exceedingly  painful  scald. 

The  careful  sterilisation  of  all  vessels  is  imperative.  Toluene  is  a  useful  steri- 
lising agent.  It  is  conveyed  into  the  cold  vessels  in  a  current  of  steam.  The 
steam  and  toluene  first  condense  on  the  cold  surface  of  the  vessels,  and,  as  the 
temperature  rises,  both  are  vaporised  and  swept  away,  thus  ensuring  complete 
sterility.  By  means  of  a  little  ingenuity,  the  water  never  comes  into  contact  with 
air,  from  the  beginning  of  the  distillation  proper  until  it  is  poured  out  for  making 
the  injection  solution.* 

*  Water  prepared   in  this  way  can  be  obtained  from  J.  Patterson,  51,  Church  Street,  Stoke 
Newington,  N. 


298  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF    SYPHILIS. 

The  water  may  be  kept  for  several  days  without  deterioration,  provided  that 
the  vessel  be  not  opened. 

Before  pouring  out  the  water,  the  mouth  of  the  vessel  should  be  carefully  wiped 
with  sterile  wool. 

The  reaction,  again,  is  largely  influenced  by  the  preparation  of  the  patient 
beforehand,  and  bj^  the  degree  of  alkalinity  of  the  fluid  injected. 

This  corresponds  with  the  well  recognised  fact  that  patients  who  have  been  well 
prepared  for  anaesthetics  suffer  less  than  those  who  have  not. 

Toxic  Manifestations  in  the  Pre-pure  Water  Days. 

Before  taking  the  precaution  of  using  water  which  had  been  prepared  in  the 
above  fashion,  I  encountered  the  following  toxic  effects  : — 

(a)  A  patient  in  a  perfectly  healthy  condition,  developed  acute  muscular  pain 
in  his  left  pectoralis  major  muscle,  three  days  after  the  injection.  A  fortnight  after 
the  first,  a  second  was  given,  when  the  pain  above  described  spread  to  almost  every 
muscle  of  the  body,  like  influenza.  Muscular  pain  is  common  after  salvarsan,  and 
usually  starts  in  the  small  of  the  back,  and  resembles  lumbago.  As  a  ride  it  lasts 
only  a  day  or  two. 

It  is  quite  likely  that  these  symptoms  are  produced  by  a  toxic  action  on  the 
sensory  nerves.  Any  pain  caused  by  a  sj'philitic  lesion,  such  as  sciatica  for  instance, 
is  sure  to  be  aggravated,  for  the  time  being,  by  an  injection,  and  it  is  very  difficult 
to  say  whether  this  is  due  to  a  toxic  action  on  the  nerve,  or  to  reactionary  inflam- 
mation around  it. 

(b)  Cases  of  Herpes  zoster  have  been  described,  which  suggest  a  toxic  action 
of  the  drug  on  the  posterior  horn  cells  ;  but  far  more  common  are  cases  of  Herpes 
febrilis,  on  both  the  face  and  genitalia.  Herpes  genitalis  is  so  common  in  patients 
who  have  had  venereal  diseases,  that  whether  the  occurrence  after  "  60G  "  is 
projiter  hoc  or  post  hoc  cannot  be  with  certainty  established,  because  we  are  quite 
in  the  dark  as  to  the  real  nature  of  the  condition.  ' 

I  have  had  four  cases  of  Herpes  genitalis  breaking  out  on  the  site  of  the  chancre, 
after  it  had  completely  healed  under  salvarsan,  and  one  of  them  had,  at  the  same 
time.  Herpes  febrilis  on  the  lips.  On  two  occasions  I  have  seen  Herpes  zoster  succeed 
salvarsan,  and  I  have  had  three  cases  in  which  this  condition  followed  mercurial 
treatment. 

(c)  Case  47. — A  patient  in  perfect  health  developed  a  bad  headache  on  the  third 
day  after  an  intravenous  injection  of  salvarsan,  an  intramuscular  one  having  been 
given  six  months  previously.     He  went  to  bed,  became  feverish,  almost  unconscious. 


TOXIC    SYMPTOMS   OF    SALVARSAN    AND    NEO-SALVARSAN.  299 

talked  gibberish,  and  had  widely  dilated— not  reacting— pupils  ;  at  times  he  was 
almost  aphasic,  but  there  were  no  paralyses.  A  few  days  later,  he  was  quite 
normal  again,  and  has  remained  so.  Prior  to  the  attack  he  had  undergone  severe 
mental  strain,  which,  no  doubt,  was  an  exciting  cause.  I  think  this  must  be 
regarded  as  a  result  of  the  toxic  influence  of  salvarsan  upon  the  sensorium  primarily 
injured  by  the  endotoxines  in  the  distilled  water,  and  not  as  an  inflammatory 
reaction  of  the  meninges,  as  in  a  case  of  incipient  pachymeningitis,  because  the 
immediate  reaction  was  so  severe. 

(d)  The  toxicity  of  salvarsan  is  greatly  increased  by  the  presence  of  organisnisother 
than  those  which  it  is  destined  to  destroy.  For  instance,  if  a  patient  with  influenza 
be  injected,  the  reaction  is  violent ;  or,  if  a  patient  with  septic  tonsillitis  be  injected, 
he  may  run  a  temperature  for  some  days,  and  the  tonsillitis  may  become  very  much 
aggravated.  Bronchitis  has  likewise  occurred  after  injection,  due  to  a  lighting 
up  of  some  dormant  pathogenic  organism.  It  is  possible  that  some  cases  of 
encephalitis  may  be  caused  in  the  same  way,  and  that  their  onset  may  be 
stimulated  by  the  endotoxines  in  the  distilled  water. 

Most  important  work  on  the  action  of  bacterial  endotoxines,  in  increasing  the 
toxicity  of  salvarsan,  has  recently  been  undertaken  by  YakimofE."  ^ 

The  first  endotoxine  experimented  with,  was  that  obtained  by  a  twenty-four 
hours'  broth-culture  of  Bacillus  coli  communis.  The  tolerant  dose  of  both  this 
and  salvarsan  being  ascertained,  such  doses  were  given  intravenously  to  animals, 
mixed  and  separately,  at  varying  intervals,  with  the  residt  that  a  dose  of  salvarsan 
which  was  ordinarily  non-toxic,  became,  on  the  addition  of  a  harmless  close  of 
endotoxine,  lethal.  Toxicity  was,  in  fact,  increased  two  and  a  half  times.  If  the 
animals  were  infected  with  protozoa,  the  toxicity  was  still  further  increased.  In 
mice,  for  instance,  slightly  infected  with  trypanosomes,  the  residt  of  injecting 
endotoxine  with  salvarsan  was  to  increase  the  toxicity  of  the  latter  eight  times, 
and,  if  markedly  infected,  sixteen  times.  The  same  results  were  produced  by 
giving  the  endotoxine  intravenously,  and  the  salvarsan  subcutaneously.  The  endo- 
toxine of  Bacillus  pyocyaneus  increased  the  toxicity  of  salvarsan  three  and  a  half 
times,  and  still  higher  if  the  animals  had  trypanosomiasis.  Other  bacteria,  such 
as  Staphylococcus  aureus,  Bacillus  subtilis,  etc.,  were  also  found  to  increase 
toxicity  in  varying  degrees  ;    while,  on  the  contrary,  Bacillus  tetragenus  was  inert. 

These  experiments  suffice  to  show  that  Wechselmann's  statement,  that  the 
reaction  following  injection  is  due  to  endotoxines  in  the  distilled  water,  stands 
correct.  They  also  corroborate  the  view  that  the  reaction  depends  somewhat  upon 
the  number  of  protozoa  present. 

Another  point  has  struck  me  about  these  toxic  symptoms,  that  they  have 


300  THE    BI0L0C4Y,    CLINICAL   ASPECT   AND   TREATMENT   OF    SYPHILIS. 

occurred  only  after  the  second  injection,  although,  in  the  majority  of  cases,  they  were 
foreshadowed  after  the  first.  This  is  not  due  to  anaphylaxis,  as  had  been  thought, 
but  to  the  second  injection  of  endotoxines  in  the  distilled  water  still  further  increasing 
the  toxicitj^  of  the  salvarsan. 

(e)  True  epileptiform  attacks  have  occurred  after  salvarsan,  and  are  probably 
dependent  upon  inherited  tendency,  for  they  may  occur  after  any  exciting  cause ; 
therefore  a  patient  who  has  had  epileptic  fits,  definitely  not  syphilitic  in  origin, 
should  never  receive  an  injection.     I  have  had  two  such  cases. 

(/)  A  case,  diagnosed  as  cerebro-spinal  syphilis,  died  three  days  after  an  intra- 
muscular injection  of  salvarsan.  The  patient  was  extremely  ill  when  the  injection 
was  given,  and  it  was  only  prescribed  as  a  last  resource.  Post-mortem,  he  was 
found  to  have  primary  sarcoma  of  a  suprarenal,  with  secondary  deposits  in  the 
brain  and  meninges.  The  cortical  cells  in  this  case  also  showed  changes  produced 
by  a  toxine,  and  here  again  the  resisting  power  of  the  nerve  cells  must  have  been 
very  considerably  below  par,  and,  of  course,  the  case  ought  never  to  have  been 
injected. 

(9)  On  the  digestive  tract,  salvarsan  may  occasionally  act  in  a  toxic  manner,  and 
here  again  the  initial  reaction  is  always  severe.  Two  cases  had  persistent  vomiting 
and  rise  of  temperature  for  three  days,  and  then  they  became  jaundiced,  due  to  a 
catarrh  of  the  bile  ducts.  Both  occurred  after  the  second  injection,  and  both  had 
severe  initial  reactions.  Aladow*  showed  that  in  dogs  which  had  been  operated 
upon  to  demonstrate  the  secretion  of  the  stomach,  an  injection  of  salvarsan  inhibited 
both  the  secretion  of  gastric  juice  and  bile,  and  could  lead  to  catarrh  of  the  stomach 
and  biliary  system,  which,  ha\ang  once  been  set  up,  did  not  disappear  until  the 
arsenic  had  been  eliminated.  This  shows  the  extreme  importance  of  not  injecting 
a  patient  with  a  disease  of  either  the  liver  or  of  the  stomach. 

If  a  patient  has  fasted  too  long,  the  administration  of  salvarsan  may  cause  a 
sudden  fall  in  blood  pressure,  and  may  cause  the  patient  to  be  immediately  sick. 
Patients  with  severe  secondary  anaemia,  and  those  who  feel  very  ill,  are  liable  to 
be  sick  during  or  immediately  after  the  injection.  Sleeplessness  is  a  very  conmion 
symptom  after  "  606." 

The  above  are  the  only  examples  of  the  evil  action  of  salvarsan  which  I  have 
experienced,  and,  in  the  last  case,  it  should  certainly  never  have  been  used. 

Toxic  Manifestations  in  the  Post-pure  Water  Days. 

The  toxic  manifestations,  which  have  followed  salvarsan  and  neo  salvarsan, 
since  only  pure  water  has  been  in  use,  will  now  be  described. 


TOXIC    SYMPTOMS   OF   SALVARSAN   AXD   NEQ-SALVARSAN.  301 

(a)  If  the  patient  lias  had  merc\irial  stomatitis  while  salvarsan  or  neo-salvarsan 
is  being  used,  almost  directly  after  the  injection  has  been  given,  the  patient 
experiences  the  most  acute  pain  in  his  gums.  This  sets  in  half  to  two  hours  after 
the  injection,  and  lasts,  may  be,  for  several  hours. 

When  several  injections  of  neo-salvarsan  are  given  quickly  after  one  another, 
occasionally  it  may  happen  that,  after  the  sixth  or  seventh  injection,  the  patient 
complains  of  electric  shocks  down  the  arms  and  legs,  aSecting  only  the  hands  and 
feet,  when  the  limbs  are  outstretched.  Attacks  of  giddiness  sometimes  accompany 
these  symptoms.  In  a  few  of  the  cases  I  have  had,  the  symptoms  have  not  come 
on  for  several  weeks  after  the  last  injection  has  been  given.  As  a  rule,  the  symptoms 
last  for  some  time,  but  ultimately  always  disappear.  The  administration  of 
m,ercury  afterwards  is  apt  to  impede  their  disappearance,  as  the  symptoms  are 
undoubtedly  due  to  a  metallic  neuritis. 

{b)  Acne  vulgaris  and  furuncidosis  are  not  at  all  uncommon  after  "  606."  This 
is  probably  owing  to  the  tonic  action  of  the  drug,  as  many  patients  only  have 
boils  when  they  are  in  the  best  of  health.  But  another  explanation  is  equally 
likely  :  salvarsan  breaks  up  the  lipoid-globulin  in  the  serum — the  carrier  of  all  the 
protective  substances — thereby  decreasing  the  resistance  to  staphylococci.  Many 
cases  of  gonorrhoea  are  aggravated  by  salvarsan,  undoubtedly  for  the  same  reason, 
and  the  explanation  just  given  will  account  for  the  relative  ease  with  which 
patients  who  have  had  salvarsan  contract  other  diseases.  I  have  had  several  cases 
who  have  contracted  follicular  tonsillitis,  Vincent's  angina,  influenza,  measles,  and 
scarlet  fever,  so  that  the  occurrences  of  these  diseases  have  been  more  than  mere 
coincidences. 

(c)  Toxic  erythemata  are  rare  after  salvarsan,  but  I  have  had  one  case  which 
developed  tjrpical  exfoliative  dermatitis.  Toxic  erv'themata  occurring  after  the 
first  or  second  injection  in  the  generalisation  stage,  are  doubtless  often  due  to  the 
endotoxines  liberated  from  the  death  of  the  sxi^hilitic  organisms,  and,  as  a  rule,  a 
rash  does  not  appear  after  the  subsequent  injections ;  consequently  there  is  no 
harm  in  repeating  them.  It  is  quite  easy  to  distinguish  a  toxic  erythema  produced 
by  the  drug  from  one  produced  by  the  spirochaetal  endotoxine,  since  the  former 
is  a  true  toxic  erythema  and  always  affects  the  backs  of  the  hands,  and  is  not  unlike 
Erythema  multiforme,  while  the  latter  is  a  true  reactionary  inflammation,  conse- 
quently the  rash  is  merely  an  aggravation  of  the  already  existing  syphilitic  lesions. 

The  severe  toxic  erythema  due  to  the  arsenic  does  not  generally  come  on  until 
after  the  patient  has  had  several  injections  at  frequent  intervals.  The  rash  may 
appear  soon  after  the  last  injection,  or  not  for  weeks,  and  the  palmar  h^'perkeratosis 
not  for  months.     I  have  seen  a  case  in  which  exfoliative  dermatitis  followed  the 


302  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   SYPHILIS. 

first  injection  of  neo-salvarsan,  but  the  drug  used  was  the  French  substitution 
product.  From  the  English  substitution  products,  I  have  seen  five  cases  of 
exfohative  dermatitis,  one  of  which  terminated  fatally.  None  of  these  cases  had 
had  more  than  two  injections. 

(d)  An  odd  point  about  salvarsan  and  neo-salvarsan  is,  that  patients  who  have 
undergone  a  course  some  time  ago  are  very  apt  to  develop  toxic  symptoms,  when 
an  interval  is  allowed  to  elapse,  and  the  course  is  repeated.  This  is  one  of  the 
reasons  why  I  prefer  to  give  at  one  time  all  the  salvarsan  the  patient  is  to  have. 
The  toxic  symptoms  are  fever,  rheumatic  and  neuritic  pains,  with  headache  and 
vomiting.  In  some  of  the  cases,  the  symptoms  increase  as  the  number  of  injections 
goes  up  ;  but,  as  a  rule,  the  symptoms  are  pronounced  for  the  first  two  injections, 
and  then  diminish  as  the  injections  increase.  Women  are  more  susceptible  to 
"  606  "  than  men  are,  but  this  susceptibility  is  not  increased  during  the  menstrual 
period,  therefore  there  need  be  no  fear  in  giving  an  injection  at  this  time. 

(e)  I  have  seen  four  cases  in  which  an  ulcer  in  the  mouth  appeared  after  "  606," 
and  in  all  four  it  was  situated  just  behind  the  last  molar  tooth. 

(/)  In  three  cases,  I  have  seen  small  patches  of  leucoplakia  on  the  lips,  tongue, 
and  cheek,  caused  by  salvarsan,  but  never  anything  in  the  way  of  an  approaching 
malignant  lesion,  as  I  have  yet  to  see  a  case  in  which  the  toxic  symptoms  have  not 
sooner  or  later  disappeared.  In  two  cases,  I  have  seen  transverse  ridges  appear  on 
the  nails,  and  I  once  had  a  case  in  which  Alopecia  areata  appeared  to  be  associated 
with  the  administration  of  neo-salvarsan. 

ig)  I  have  seen  a  few  rather  odd  cases,  which  might  with  advantage  be  mentioned. 
A  patient  had  two  intravenous  injections  of  salvarsan,  one  in  each  arm,  and  as 
the  operator  had  had  a  difiiculty  in  getting  into  the  vein,  both  had  been  exposed 
through  a  small  incision.  Some  weeks  later,  the  patient  consulted  me  about  her 
arms,  and  where  the  incisions  had  been  made  were  large  Condylomata  lata.  It 
appeared  that  the  wounds  never  healed  by  first  intention,  and,  owing  to  the 
injury  caused,  syphilitic  lesions  had  developed  locally  ;  and,  owing  to  the  con- 
tinuous oozing  from  places  which  had  not  healed  properly,  the  papules  'had 
developed  into  condylomata. 

In  another  case,  also  in  a  woman,  wherever  I  punctured  a  vein,  a  crop  of  Lichen 
planus  lesions  appeared  sometime  afterwards.  I  once  had  a  patient  with  syphilitic 
palmar  papular  hyperkeratosis,  the  most  resistant  syphilide  to  treatment  that  I  know, 
and  he  invariably  developed  a  typical  syphilitic  lesion  wherever  he  injured  his  hand, 
and  a  lesion  always  resulted  in  the  spot  where  I  pricked  his  finger  for  blood.  This 
patient  had  seventeen  injections  of  salvarsan  and  thorough  mercurial  treatment, 
and  yet  the  papules  still  persisted  in  coming  out,  and  his  blood  was  always  positive. 


TOXIC    SYMPTOMS    OF    SALVARSAN   AND    XEO-SALVARSAN.  303 

The  patient  married,  and  has  already  had  two  children,  who  are  both  clinically  and 
serologically  sound,  in  spite  of  the  fact  that  the  father  still  gives  a  +  +  +  Wasser- 
mann  reaction. 

Syphilitic  patients,  whether  in  the  early  or  late  stages  of  the  disease,  may  get 
general  enlargement  of  the  lymphatic  glands  after  salvarsan,  doubtless  due  to 
the  production  of  lymphocytes,  which  salvarsan  stimulates. 

Patients  with  peripheral  nerve  lesions,  not  of  syphilitic  origin,  and  of  syphilitic 
origin  if  late,  often  have  their  symptoms  very  much  aggravated  by  salvarsan. 

Peripheral  neuritis,  such  as  sciatica,  if  aggravated,  does  not  very  much  matter, 
as  the  trouble  will  in  time  disappear,  but  when  it  is  the  eighth  nerve  that  is  affected, 
irreparable  damage  may  be  done.  I  have  had  two  cases  of  old  syphilitics  with 
nerve  deafness  become  absolutely  stone  deaf  after  salvarsan.  I  have  also  known 
of  patients  over  fifty  years  of  age,  in  whom  the  deafness  was  certainly  not  of 
syphilitic  origin,  have  their  deafness  permanently  increased  by  salvarsan.  I  had 
a  case  of  congenital  syphilitic  deafness,  in  which  the  ear  trouble  did  not  commence 
until  the  patient  was  32  years  of  age,  and  he  went  stone  deaf  after  the  second  injection 
of  salvarsan.  I  have  seen  so  much  trouble  caused  by  salvarsan  in  aural  lesions, 
that  unless  the  lesion  is  syphilitic  and  acute,  or  unless  I  am  compelled  to  give 
salvarsan  for  other  reasons,  I  always  avoid  using  it. 

{h)  Some  other  interesting  cases  are  the  following  : — Severe  nose  bleeding  after 
each  injection  of  salvarsan,  in  two  patients  with  a  high  arterial  blood  pressure.  I 
have  had  four  cases  of  bad  sexual  neurasthenia  after  salvarsan,  but,  of  course,  it  is 
very  difficult  to  say  whether  the  salvarsan  was  in  any  way  the  cause,  or  whether  the 
neurasthenia  simply  developed  because  the  patient  had  had  syphilis.  The  reason 
why  I  think  salvarsan  had  something  to  do  with  it  is,  that  some  patients  do 
become  very  much  depressed  after  "  606,"  and  all  the  four  cases  referred  to  never 
had  any  other  symptoms  except  the  chancre. 

Reactionary  Inflammation  (Herxheimer's  Reaction). 

A  phenomenon  which  now  requires  mention,  is  that  which  is  known  as  Herx- 
heimer's reaction.  Herxheimer's  reaction  was  the  term  applied  to  the  exacerbation 
of  the  generalised  rash  in  early  syphilis,  which  followed  the  first  few  inunctions  of 
mercury.  Since  the  advent  of  "  606,"  owing  to  the  greater  frequency  with  which 
the  reaction  is  seen,  more  attention  has  been  paid  to  the  phenomenon,  and  we 
now  know  that  Herxheimer's  reaction  and  the  so-called  reactionary  inflammation — 
which,  by  the  way,  is  a  far  better  term — are  synonymous. 

Prior  to  the  salvarsan  era,  all  we  knew  about  Herxheimer's  reaction  was,  that 
it   occurred   most   frequently  when  mercurial   inunctions  were  used,   rarely  when 

u 


304  THK    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

mercurial  injections  were  employed,  and  never  when  mercury  was  administered 
internally.  Practically,  the  only  mercm-ial  preparation  which  caused  the  reaction 
with  any  regularity,  when  injected  intramuscularly,  was  the  salicylate.  The  reaction 
generally  occurs  when  salvarsan  and  neo-salvarsan  are  used,  but  it  is  never  so  pro- 
nounced now  as  when  salvarsan  was  first  used. 

Mercury  reaches  the  lesions  more  quickly,  when  prescribed  in  inunctions  than  in 
injections,  and  the  reason  why  intramuscular  injections  of  the  salicylate  cause 
the  reaction  more  frequently  than  any  other  preparation,  is  due  to  the  rapidity 
with  which  the  salicylate  is  absorbed. 

As  the  reaction  is  so  constant  after  salvarsan,  it  shows  that  this  drug  is  a  more 
powerful  spiriUocide  than  mercury  is  ;  and  as  the  reaction  is  not  so  marked  with  the 
present  day  preparations,  it  shows  that  their  action  is  not  so  great  as  the  action  of 
those  which  were  first  used. 

As  the  interpretation  of  the  reaction  is  far  from  clear,  it  would  be  as  well  to 
consider  all  the  possibilities  now. 

The  reaction  occurs  at  the  site  of  the  lesion.  It  is  most  marked  in  those 
lesions  which  are  full  of  spirochaetae.  The  more  potent  the  drug  is,  and  the  more 
of  it  that  reaches  the  lesion,  the  more  pronounced  is  the  reaction. 

That  is  all  we  can  learn  from  clinical  experience.  If  a  microscopic  examination 
of  a  lesion,  before  and  during  the  inflammatory  reaction,  is  made,  other  points  can 
be  elucidated. 

The  most  noticeable  features  of  an  inflammatory  reaction  are,  the  dilatation  of 
the  capillaries,  the  beginning  of  the  breaking  down  of  the  protoplasm  of  the  plasma 
cells,  and  the  increased  acti\'ity  of  the  lymphatic  endothelial  cells.  The  sum  of 
these  changes  is  considerably  to  increase  the  dimensions  of  the  lesion. 

We  know  that  more  salvarsan  is  taken  up  by  the  syphditic  lesion  than  by  the 
healthy  tissue  around  it,  and  that  the  reaction  is  largely  dependent  upon  the  ratio 
which  exists  between  the  severity  of  the  lesion  and  the  amount  of  salvarsan  that 
reaches  it. 

The  chief  factor  in  the  inflammatory  reaction  is  the  vascidar  dilatation,  since, 
as  Milian^  showed,  it  can  be  prevented  by  administering  adrenalin  before  the 
injection  of  salvarsan  is  given,  and  by  repeating  it  afterwards.  Moreover,  if  an 
inflammatory  reaction  has  begun  to  appear,  its  further  development  maj^  be 
checked  by  injecting  adrenalin. 

Adrenalin  acts  on  the  sympathetic  nervous  system  as,  shall  we  say,  a  stimulator. 
Certain  poisons,  acting  on  the  sympathetic  nervous  system,  cause  paralysis. 
Stimulation  produces  constriction,  paralysis  causes  dilatation  of    the    vasomotor 
fibres  of  the  sympathetic  nervous  system. 


TOXIC    SYMPTOMS   OF   SALVARSAN   AND    NEQ-SALVARSAN.  305 

In  other  words,  then,  adrenalin,  by  having  an  antagonistic  action,  neutralises 
the  poison  which  is  formed  in  a  syphihtic  lesion,  when  salvarsan  is  given. 

This  poisonous  substance  can  only  come  from  three  sources  :  (a)  the  syphilitic 
organisms  ;   (6)  the  host's  protective  cells  ;   (c)  the  drug. 

It  cannot  come  from  the  host's  protective  cells,  because  the  reaction  has  come 
and  gone,  by  the  time  the  breaking  up  of  the  protoplasm  of  the  plasma  cells  has 
reached  its  acme. 

It  is  very  unlikely  that  it  comes  from  the  drug,  as  one  would  expect  it  to  be 
more  pronounced  the  longer  the  drug  is  prescribed.  The  inflammatory  reaction 
occurs  when  mercury  is  the  drug  prescribed,  most  frequently  when  it  is  used  in  the 
form  of  inunctions,  and  then  when  the  salicylate  is  injected  intramuscularly.  The 
mercury  in  the  ointment  used  is  ordinary  metallic  mercury  ;  it  cannot  be  split  up, 
and  in  this  form  it  is  innocuous.  The  salicylate  is  again  a  very  stable  salt  and  also 
innocuous. 

The  inflammatory  reaction  is  very  marked  after  sah^arsan,  and  one  might  rush 
to  a  conclusion,  and  assume  that  it  is  due  to  the  breaking  up  of  this  complex 
molecule,  in  the  process  of  which  a  poisonous  product. is  liberated.  Against  this 
view  is  what  has  already  been  said  about  the  mercury,  and  the  fact  that  no  inflam- 
matory reaction  occurs  in  LicJien  flanus  papules  and  psoriasis  lesions,  which  respond 
to  salvarsan  before  they  disappear.  The  inflammatory  reaction  is  most  marked 
after  the  second  injection  of  salvarsan.  There  may  be  none  after  the  third,  although 
the  dose  of  salvarsan  used  may  be  bigger,  and  the  changes  wrought  in  the  syphilitic 
lesion  raoie  pronounced. 

The  only  rational  conclusion  to  come  to  is,  that  the  inflammatory  reaction 
is  due  to  poisonous  products  liberated  on  the  death  of  the  sy|Dhilitic  organisms. 

The  first  two  injections  of  salvarsan  do  not  kill  the  main  supply  of  the  syphilitic 
organisms,  at  all  events,  not  before  the  third  injection  is  given.  Furthermore,  it  is 
mainly  the  spirochaetal  phase  of  the  Leucocytozoon  syphilidis  that  is  killed  directly  by 
the  salvarsan.  As  already  stated,  the  reaction  is  most  marked  in  those  cases  which 
are  richest  in  spirochaetae,  and  in  which  most  of  the  drug  finds  entrance.  The  greater 
the  quantity  of  drug  which  finds  entrance  to  the  lesion,  the  greater  the  number  of 
spirochaetae  that  are  killed.  Therefore,  the  inflammatory  reaction  is,  in  my  opinion, 
due  to  the  endotoxin?s  which  are  liberated  from  the  spirochaetae  as  they  are  killed. 

Other  evidence  in  favour  of  the  view  just  enunciated,  is  the  fact  that  the  spiro- 
chaetae contain  an  hydroxyl  group  in  their  chemical  structure,  which  the  other 
phases  do  not.  Metals  are  fixed  on  to  these  hydroxyl  groups,  and  with  greater 
ease,  the  freer  they  are.  The  rate  of  adsorption  of  the  metal  will  play  a  rdle,  and 
so  will  the  quantity  which  can  be  injected. 

u2 


300  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF    SYPHILIS. 

The  mercuiy  used  in  inunctions  is  metallic  mercury,  and  therefore  can  be 
readily  fixed  by  the  hydroxyl  groups  of  the  spirochaetae.  Mercury  salicylate  is 
quickly  absorbed,  but  it  must  be  broken  down  and  the  metal  set  free,  before  it  can 
act,  hence  the  inflammatory  reaction  is  not  so  regular  when  this  preparation  is 
used  as  when  inunctions  are  employed.  In  salvarsan,  relatively  enormous  quan- 
tities of  the  metal  arsenic  can  be  administered,  simply  because  it  exists  in  a  colloidal 
state.  As  soon  as  the  "606"  reaches  the  syphilitic  lesion,  its  complex  molecule 
becomes  broken. 

The  arsenic  is  liberated  and  gets  fixed  to  the  free  hydroxyl  groups.  This  is 
also  the  reason  why  the  spirochaetal  phase  stains  with  silver  nitrate,  and  the  other 
phases  do  not. 

When  a  metal  becomes  fixed  to  the  hydroxyl  groups  of  the  spirochaetae,  it 
not  only  robs  the  molecule  of  some  of  its  oxygen,  but  also  rapidly  alters  its  normal 
arrangement  of  ions,  hoice  the  protoplasm  of  the  organism  becomes  disintegrated, 
and  the  parasite  is  killed. 

Endotoxines  are  liberated  from  the  death  of  all  organisms.  They  all  act  as 
poisons,  and  all  appear  to  paralyse  the  vasomotor  fibres  of  the  sympathetic  nervous 
system,  in  the  area  in  which  they  are  generated.  Dilatation  of  the  vessels  results 
in  an  erythema,  which  can  be  recognised  by  the  naked  eye.  Erythema  in  an  already 
inflammatory  lesion,  will  increase  the  dimensions  of  that  lesion,  and  the  patient's 
trouble  appears  for  the  time  being  to  be  aggravated.  This  is  what  is  known  as 
Herxheimer's,  or,  better,  reactionary  inflammation. 

The  syphilitic  reactionary  inflammation  differs  from  the  so-called  focal  reaction, 
which  one  often  sees  after  the  administration  of  a  vaccine,  for  instance.  The  latter 
is  due  to  the  breaking  down  of  the  already  existing  lipoid-globulin  or  protective 
substance,  and  the  ultimate  formation  of  a  new  product.  In  the  interim,  or 
during  the  time  in  which  there  are  no  protective  substances,  the  organisms  naturally 
flourish  to  their  heart's  content,  hence  follows  an  aggravation  of  the  areas  which 
they  are  inhabiting. 

It  is  only  old  lipoid-globulin  which  can  in  this  way  be  broken  up — that  is, 
lipoid-globulin  especially  rich  in  COOH  groups.  Now,  in  the  case  of  any  substance 
having  anything  like  the  same  stereo-chemical  molecular  configuration  as  the  pro- 
tective lipoid-globulin,  and  a  specific  vaccine  has  this,  the  richer  the  protective 
siibstance  is  in  COOH  groups,  the  greater  the  ease  with  which  the  molecules  of  the 
vaccine  can  become  attached  to  it.  The  molecules  become  attached  by  adsorption. 
Adsorption  results  in  precipitation  of  the  adsorbed  substances,  and  hydi'olysis  soon 
follows.  The  more  vaccine  that  is  used,  the  more  protective  substance  there  is 
adsorbed ;  and  the  more  quickly  it  is  hydrolysed,  the  more  marked  the  focal  reaction. 


TOXIC    SYMPTOMS   OF   SALVARSAN    AND    NEO-SALVARSAN.  307 

The  focal  reaction  following  a  vaccine  is  due  then  to  the  temporary  inhibition 
of  the  host's  protective  substance,  and  this  allows  the  organisms  to  flourish,  and 
to  aggravate  the  condition. 

Why  cannot  this  theory  also  serve  to  explain  the  syphilitic  inflammatory 
reaction  ? 

The  inflammatory  reaction  is  most  marked  in  the  early  stage  of  the  disease. 
In  the  early  stage  of  syphilis,  salvarsan  does  not  break  up  the  existing  lipoid- 
globulin,  at  any  rate  the  first  two  or  three  injections  do  not  do  so. 

It  is  in  the  late  stages  of  syphilis  that  the  first  and  second  injections  of  salvarsan 
break  up  the  lipoid-globulin  of  the  serum,  in  the  stage  in  which  the  inflammatory 
reaction  is  often  absent,  and  never  is  very  marked. 

The  interval  which  exists  between  the  breaking  down  of  the  old  lipoid-globulin 
by  salvarsan  and  the  production  of  the  new  lipoid-globulin,  is  only  a  matter  of  a 
few  days  at  the  most.  The  development  of  the  syphilitic  organisms  requires  many 
more  than  a  few  days,  hence  a  focal  reaction  can  never  be  caused  by  their  multiplica- 
tion. Moreover,  the  spirochaetae — the  main  cause  of  the  symptoms — are  vanquished 
by  the  first  two  injections,  in  spite  of  the  fact  that  there  has  been  an  inhibition  of 
the  host's  natural  protective  substances. 

Arguing  now  from  the  other  side.  After  a  vaccine,  a  focal  reaction  is  most 
marked  in  the  late,  not  in  the  early,  stages  of  the  infection.  If  the  protective 
lipoid-globulin  has  been  recently  renewed,  a  focal  reaction  does  not  occur.  Further, 
a  vaccine  does  not  directly  kill  the  organisms  it  is  sent  to  attack,  as  salvarsan  does 
the  spirochaetae.  Lastly,  bacteria,  such  as  gonococci,  can  multiply  rapidly  in 
twenty-four  hours,  and  hence  are  easily  able  to  aggravate  the  symptoms. 

Neuro-Eecurrences. 

An  inflammatory  reaction  must  not  be  mistaken  for  the  onset  of  symptoms 
which  do  not  make  their  first  appearance  until  some  time  has  elapsed,  after  treat- 
ment has  been  suspended.  This  now  brings  me  on  to  describe  the  neuro-recurrences, 
which  many  observers  incorrectly  have  regarded  as  a  form  of  inflammatory  reaction. 
Neuro-recurrences  are  lesions  of  cranial  nerves,  especially  the  eighth  and  second, 
and  they  have  occurred  with  greater  frequency  since  the  advent  of  salvarsan. 
The  lesions  are  primarily  meningeal,  and  the  increase  in  size  of  the  meninges,  due 
to  inflammation,  causes  pressure  upon  the  nerves  as  they  are  going  through 
bony  canals.  Pressure  on  a  nerve  first  produces  neuritis,  and,  if  continued, 
atrophy. 

If  the  reader  has  read  Chapter  XXIIT,  he  will  remember  that  the  body  can  be 


308  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT    OF    SYPHILIS. 

divided  into  two  parts  :  {a)  systemic  ;  (b)  nervous ;  that  there  is  little  com- 
munication between  the  two  ;  that  the  occurrence  of  lesions  in  the  nervous  part 
depends  largely  upon  the  quantity  and  quality  of  the  antibody  circulating  in  the 
systemic  part,  and  that  a  ratio  exists  between  the  kind  of  treatment  prescribed 
and  the  quantity  of  the  antibody  circulating  in  the  systemic  part. 

If  the  treatment  is  sufficient  to  check  the  production  of  antibodies,  and  is 
only  prescribed  after  the  organisms  have  reached  the  nervous  system,  the  organisms 
in  the  nervous  system  will  be  rid  of  one  of  their  enemies,  and  will  therefore  be 
able  to  multiply  and  develop,  more  or  less  at  their  owia  free  will.  The  so-called 
neuro -recurrences  arise  in  this  way :  they  are  true  syphilitic  meningeal  lesions, 
afiecting  secondarily  certain  cranial  nerves,  and  are  exactly  analogous  to  other 
meningeal  lesions  of  the  brain  and  cord,  to  which  I  have  recently  attempted  to  draw 
so  much  attention. 

Neuro-recurrences  occur  more  frequently  after  salvarsan  than  after  mercury, 
but  they  only  occur  after  the  former,  if  it  has  been  inadequately  administered — a 
tremendous  support  in  favour  of  my  argument  that,  owing  to  the  inadequate  and 
injudicious  manner  in  which  salvarsan  is  being  used  in  this  country,  nervous  diseases 
are  on  the  increase. 

Oddly  enough,  most  observers  admit  that  the  cranial  nerve  lesions  have  been 
more  common  since  salvarsan  has  been  in  vogue,  but  yet  my  statement  that 
nervous  diseases  are  on  the  increase  has,  even  amongst  neurologists,  met  with  the 
greatest  opposition.  Perhaps  in  twenty  years'  time,  when  it  is  too  late,  everyone 
will  realise  that  the  connection  between  the  onset  of  nervous  lesions  and  the 
administration  of  treatment  is  a  very  firm  one. 

Owing  to  the  fact  that  amaurosis  has  occurred  after  the  use  of  atoxyl  and 
arsacetin,  there  was  at  first  a  very  strong  suspicion  that  salvarsan  might  be  followed 
by  the  same  result.  There  has  been  but  one  case  in  which  optic  atrophy  followed 
an  injection  of  "  606."  A  female,  aged  22,  under  the  care  of  Prof.  Finger,  received 
on  July  6th,  1910,  0'4  grm.  of  salvarsan  in  an  emulsion,  for  a  malignant  form  of 
syphilis  of  long  duration.  On  October  5th,  that  is,  three  months  later,  she 'com- 
plained of  dimness  of  vision  in  both  eyes  ;  the  pupils  were  imequal,  and  there  was 
early  bilateral  optic  atrophy.  It  should  be  mentioned  that  this  patient,  throughout 
the  previous  year,  had  been  rigorously  treated  with  organic  arsenical  compounds, 
having  received  thirty  injections  of  arsacetin  and  sixty-nine  of  "  enesol  "  (salicyl- 
arsenate  of  mercury).  Other  than  this  instance,  there  has  not  been  a  single 
case  of  optic  atrophy  following  salvarsan,  due  directly  to  the  drug,  although  the 
number  of  injections  given  must  now  run  well  into  seven  figures.  It  is  a  well  known 
fact,  that   an   over-sensitiveness  of   the   eyes   to   arsenic   sometimes   occurs   after 


TOXIC    SYMPTOMS    OF   SALVARSAN   AND    NEO-SALVARSAN.  309 

continuous  treatment  with  the  organic  synthetic  compounds,  and  it  has  been  shown 
that  arsacetin  is  more  liable  to  produce  optic  atroph}'  in  cases  which  had  been 
previously  treated  with  atoxyl,  than  in  fresh  cases,  so  it  is  more  than  likely  that 
tliis  single  case  was  determined  by  the  previous  arsenic  treatment. 

Lesions  of  the  optic  nerve  and  auditory  nerve  have  occurred  after  "  606,"  but 
they  are  not  toxic  manifestations,  since  they  are  unilateral,  and  improve  either  under  a 
second  injection,  or  under  treatment  with  mercury.  These  optic  and  auditory  lesions 
are  of  the  nature  of  a  neuritis.  The  optic  neuritis  often  starts  with  conjunctivitis, 
photophobia,  and  headache,  making  objects  appear  hazy.  If  the  trunk  of  the 
eighth  nerve  is  affected,  symptoms  referable  to  both  of  its  branches  will  be  manifest. 
If  the  cochlear  alone  is  affected,  then  deafness  may  come  on  suddenly,  but 
more  often  gradually.  Its  course  may  be  short,  or  the  deafness  may  so  slowly  get 
worse  that  the  patient's  attention  is  scarcely  drawn  to  it.  When  the  vestibular  nerve 
is  involved,  the  patient  complains  of  tinnitus,  giddiness,  and  vomiting  ;  the  vomiting 
is  irrespective  of  food,  and  is  usually  worst  on  getting  up  in  the  morning,  owing  to 
the  change  of  posture  causing  a  disturbance  in  the  semicircular  canals.  In  the 
early  stage  nystagmus  is  present. 

The  following  case  is  typical  of  a  lesion  of  the  trunk  of  the  auditory  nerve  : — 

Case  21. — L.  M.,  female,  aged  35,  came  to  the  hospital  with  a  psoriasiform  syphilide 
on  her  legs.  Two  years  before,  the  patient  contracted  syphilis,  and  was  treated  for 
eight  weeks  with  inunctions  in  the  General  Hospital,  Yarmouth,  where  she  developed 
double  iritis.  Two  months  after  leaving  hospital,  condylomata  appeared  around 
the  anus  and  between  the  toes.  Since  then  the  patient  had  not  been  treated.  It 
was  noticed  that  she  did  not  seem  to  hear  very  well,  and  on  inquiry  she  stated  that 
she  had  been  deaf  in  the  right  ear  for  six  months.  The  deafness  had  come  on 
gradually  and  was  slowly  getting  worse,  and,  at  the  same  time  as  it  commenced, 
noises  in  the  ear  were  experienced  and  the  patient  was  much  troubled  with  attacks 
of  giddiness,  which  prevented  her  from  going  out.  The  patient  always  had  the 
feeling  as  if  she  was  going  to  fall  forwards,  and  she  actually  did  so,  on  two  occasions. 
The  giddiness  and  vomiting  were  always  worse  on  getting  up  in  the  morning,  and 
the  latter  occurred  during  the  day,  quite  irrespective  of  food.  These  symptoms, 
except  the  giddiness,  were  increasing  in  severity.  ^Vhen  I  first  saw  her  she  had 
slight  nystagmus,  which  later  disappeared. 

Examination  of  the  ears  was  kindly  undertaken  for  me  by  Mr.  S.  R.  Scott. 
The  left  external  meatus  showed  old  stenosis,  but  there  was  no  defect  of  hearing 
on  this  side,  and  electrical  reactions  were  normal.  There  was  a  marked  reaction 
to  the  caloric  test  in  one  minute  at  115°  F.,  the  patient  falling  to  the  right.  On  the 
right  side  hearing  was  diminished  ;    no  artificial  Rhomberg's  sign  or  nystagmus 


310  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT    OF   SYPHILIS. 

was  produced  by  syringing  for  three  minutes  with  water  at  118°  F.  ;  the  electrical 
reactions  of  the  vestibular  nerve  were  sluggish,  but  had  not  c^uite  disappeared. 
All  pointed  to  a  neuritis  of  the  trunk  of  the  eighth  nerve  on  the  right  side,  most 
probably  of  syphilitic  origin.  This  case  is  instructive,  since  the  patient  had  never 
had  "  606,"  would  not  have  complained  of  her  nerve  condition  had  her  attention 
not  been  drawn  to  it,  and  had  never  connected  it  with  her  disease.  Under  mercurial 
injections  all  symptoms  referable  to  the  vestibular  branch  cleared  up,  but  the 
deafness  remains  much  about  the  same,  and,  like  so  many  of  these  cases,  is  much 
less  on  one  day  than  on  another. 

I  also  saw  a  man  who  became  gradually  deaf  in  one  ear  four  months  after  the 
appearance  of  the  sore,  and  who  had  had  no  treatment  at  all.  His  deafness  almost 
completely  disappeared,  three  months  after  two  intravenous  injections  of  salvarsan 
and  eight  intramuscular  injections  of  grey  oil. 

The  cochlear  branch  is  not  infrequently  implicated  alone,  much  more  commonly 
so  than  the  vestibular. 

Apart  from  a  neuritis  of  the  eighth  and  second  cranial  nerves,  of  which  the 
former  is  more  frequent  than  the  latter,  the  other  cranial  nerves  are  involved  in  the 
following  order  of  frequency  :    seventh,  third,  fourth,  fifth,  and  sixth. 

When  a  neuritis  of  a  cranial  nerve  sets  in  after  "  606,"  in  96  per  cent,  of  cases, 
it  does  so  within  the  first  four  months.  The  cases  are  almost  invariably  in  the 
early  generalisation  stage  of  syphilis,  the  Wasserniann  reaction  is  generally  negative, 
and  the  patients  have  usually  had  only  one  injection.  This  marked  similarity  as 
regards  onset  and  occurrence  finds  its  explanation,  if  we  consider  the  frequency  of 
neuritis  in  syphilis  before  the  days  of  "  606." 

So  slight,  so  gradual  in  onset  and  progression,  may  symptoms  of  a  neuritis  of 
the  cranial  nerves  be,  that  the  patient  does  not  connect  them  vdth  his  disease,  and 
consequently  does  not  draw  his  doctor's  attention  to  them.  By  astute  observers 
they  have  been  noticed  and  described,  but,  beyond  this,  cranial  nerve  lesions  in 
sj'philis  have  not  received  the  recognition  due  to  them. 

Their  occurrence  after  "  606  "  made  syphilologists  examine  their  cases  more 
thoroughly  before  treatment,  with  the  astonishing  result,  that  the  frequency  of  such 
lesions  was  nearly  as  great  as  that  of  those  reported  to  be  due  to  salvarsan.  They 
noticed  further  that  these  nerve  affections  were  not  uncommon  in  the  early 
generalisation  stage,  setting  in  within  a  year  of  infection,  that  they  were  more  often 
unilateral  than  bilateral,  and  were  just  as  common  in  patients  who  had  not  had 
any  mercury  as  in  those  who  had,  although  it  has  more  than  once  been  stated,  that 
they  were  more  common  after  the  use  of  soluble  preparations  than  they  were  after 
the  insoluble  salts  of  mercury.     These  facts  show  that  nerve  lesions  are  syphilitic 


TOXIC    SYMPTOMS    OF   SALVARSAN   AND   NEO-SALVARSAN.  311 

manifestations,  and  that  their  occurrence  after  "  60G  "  signifies  inadequate  treat- 
ment, and  that  they  are,  in  short,  neuro-recurrences. 

Igersheinier^  showed  that  atoxyl  amblyopia  was  a  simple  progressive  atrophy 
of  the  optic  nerve,  and  that  it  might  occur  early  or  late  after  treatment.  In  only  two 
cases  was  the  amblyopia  stationary,  and  did  not  advance  further  than  a  retrobulbar 
neuritis.  Nonne,  who  had  the  opportunit}^  of  studying  the  condition  post-mortem, 
found  that  the  chief  changes  occurred  in  the  nerve  fibres  themselves,  in  the  neigh- 
bourhood of  the  chiasma.  The  changes  were  purely  parenchymatous.  The  same 
changes  could  be  produced  artificially  in  the  eyes  of  rabbits,  by  means  of  a  local 
application  of  atoxyl,  and  in  dogs  and  cats  after  subcutaneous  injections.  In  cats, 
cell-changes  were  also  to  be  found  in  the  brain  and  spinal  cord,  the  part  most 
affected  being  the  optic  thalamus. 

Neuro-recurrences  are  not  primary  nerve  lesions,  the  nerve  is  affected  mechanic- 
ally by  the  lesions  in  the  meninges.  If  the  cerebro-spinal  fluid  of  these  cases  be 
examined,  the  changes  found  will  be  those  which  one  associates  with  meningitis. 

Deafness  due  to  a  nervous  lesion  must  be  clearly  distinguished  from  middle- 
ear  deafness,  which  occurs  in  the  generalisation  stage,  either  from  involvement 
of  the  mucous  membrane  of  the  middle  ear  itself,  or  from  mucous  papules  occurring 
in  the  mouth  and  encroaching  on  the  Eustachian  tubes. 

If  the  statement,  that  these  nerve  affections  are  syphilitic  recurrences,  is  true, 
one  would  expect  to  find  that  giving  two  or  more  doses  of  salvarsan,  with  or  without 
mercury,  to  commence  with,  would  considerably  diminish  their  frequency.  Such 
is  the  case,  and  accounts  for  the  absence  or  the  presence  of  such  recurrences  in 
different  clinics.  In  the  Easter  of  1911,  I  visited  many  Continental  cities,  and  found 
that,  in  those  clinics  in  which  neuro-recurrences  were  common,  it  was  the  custom 
to  give  one  injection  of  "  606  "  and  wait  for  a  recurrence  before  giving  another, 
while,  in  those  clinics  in  which  they  were  almost  unknown,  it  was  the  custom  to  give 
two  or  more  injections  with  short  intervals,  and  to  combine  the  salvarsan  treatment 
with  mercury. 

Neuro-recurrences  followed  intramuscular  more  often  than  intravenous  injec- 
tions, because,  owing  to  the  accumulation  of  arsenic,  one  was  never  certain  when 
it  was  safe  to  repeat  the  injection. 

I  have  had  one  case  of  unilateral  optic  neuritis  within  three  months  of  giving 
one  intravenous  injection,  and  it  improved  under  further  treatment  with  mercury 
and  iodides  ;  also  one  case  of  unilateral  neuritis  of  the  trunk  of  the  acoustic  nerve, 
within  three  months  of  giving  one  intramuscular  injection,  and  it  also  improved 
under  a  second  intravenous  injection  combined  with  mercury  and  potassium 
iodide.     These  two  cases  were  in  the  early  stage  of  syphilis,  signs  of  the  primary 


312  THE    BIOLOGY,    CLINICAL    ASPECT   AND   TREATMENT   OF    SYPHILIS. 

sore  still  being  present.  Both  cases  occurred  within  the  first  four  months  of  my 
experience,  and  since  I  have  made  it  the  rule  to  repeat  the  salvarsan  within  an 
interval  of  a  few  days,  and  to  combine  it  witli  mercury,  I  have  not  had  a  single 
case  of  a  cranial  neuritis. 

Since  my  attention  was  drawn  to  these  affections  of  the  cranial  nerves,  I  have 
carefully  examined  all  cases  in  the  generahsation  stage  which  had  had  no  treatment, 
or  only  a  little  mercury.  Since  October,  1910,  I  have  seen  five  cases  of  unilateral 
optic  neuritis,  one  of  which  went  on  to  atrophy  withiai  a  few  weeks  ;  nine  cases 
in  which  the  cochlear  nerve  on  one  side  alone  was  ajJected  ;  two,  in  which  the  nerve 
affection  was  bilateral ;  and  three  in  which  the  trunk  of  the  eighth  nerve  was 
affected.  I  have  also  had  six  cases  in  which  the  facial  nerve  on  one  side  was  affected, 
but  I  have  never  seen  a  case  in  which  both  the  optic  and  acoustic  nerves  were 
involved  in  the  same  patient.     Such  a  condition  has,  however,  been  described. 

To  sum  up,  then.  Lesions  of  cranial  nerves  are  syphilitic  in  origin,  and  their 
occurrence  after  "  606  "  is  a  syphiUtic  recurrence,  secondary  to  a  meningitis,  not 
due  to  "  606,"  but  to  inadequate  treatment. 

Fatal  Cases  and  Contraindications. 

Fatal  cases  have  now  to  be  considered.  Some  fatal  cases  have  occurred 
through  faulty  technique,  by  injecting  air  or  a  solid  particle  into  a  vein,  and,  when 
salvarsan  first  came  in,  by  making  the  solution  too  acid  or  too  alkaline. 

Other  fatal  cases  have  occurred,  again,  by  giving  injections  to  patients  who 
ought  never  to  have  been  treated,  i.e.,  patients  with  advanced  cirrhosis,  cardiac 
trouble,  and  nephritis. 

A  too  pronounced  inflammatory  reaction  has  been  the  cause  of  most  of  the 
deaths  reported,  and  very  special  consideration  will  be  given  to  these. 

A  very  few  deaths  have  been  due  to  the  drug  itself,  and  I  should  very  much 
doubt  if  any  of  the  deaths  which  have  occurred  within  the  last  two  or  three  years 
have  really  been  due  to  a  toxic  action  of  the  drug.*  That  arsenic  is  found  in  the 
body  after  death  is  no  proof  that  the  death  has  been  produced  by  arsenical 
poisoning.  In  the  same  way,  a  man  with  a  wound  in  his  thigh — in  which,  fost- 
mortem,  the  tetanus  bacillus  has  been  found — who  has  been  killed  by  a  bullet  through 
the  head,  has  not  died  of  tetanus. 

The  first  group  of  cases  need  not  be  considered,  as  they  only  arise  through 
pure  carelessness. 

The  second  group  of  cases  opens  up  the  question  of  contraindications,  so  these 

will  be  now  considered. 

*  Since  the  war,  owing  to  the  substitution  products  which  have  been  employed,  this  state- 
ment does  not  hold  good  {vide  page  302). 


TOXIC    SYMPTOMS   OF    SALVARSAN    AND    NEO-SALVARSAN.  313 

To  the  drug  now  in  use,  there  are  practically  no  contraindications.  Old  age  does 
not  make  one  withhold  neo-salvarsan,  provided  the  organs  are  tolerably  sound. 
On  two  occasions,  I  have  given  as  many  as  seven  injections  of  neo-salvarsan  to  a 
patient  over  70  years  of  age,  without  experiencing  the  slightest  bad  effects. 
Naturally  a  marked  organic  disease  of  the  liver,  heart,  or  kidneys  is  a  contra- 
indication, if  the  lesions  of  these  organs  are  not  sj^hilitic  in  origin.  If  they  are 
syphilitic  in  origin,  it  will  depend  upon  whether  they  are  early  or  late  lesions  of  the 
disease.  Cholangitis  and  early  yellow  atrophy  are  not  contraindications,  but  severe 
gummatous  disease  of  the  liver  and  marked  cirrhosis  are  so. 

Syphilitic  myocarditis  is  not  a  contraindication,  but  gummatous  myocarditis 
and  severe  valvrdar  disease  may  be. 

The  nephritis  of  early  syphilis  should  be  treated  with  salvarsan.  It  is  not 
a  true  nephritis,  and  does  not  prevent  the  excretion  of  the  arsenic.  Tn  the  true  and 
late  syphilitic  nephritis,  salvarsan  should. certainly  be  withheld. 

Now  comes  a  very  important  question.  How  is  one  to  judge  when  a  late 
syphilitic  lesion  is  a  contraindication,  and  when  it  is  not  ? 

This  can  be  answered  by  estimating  the  effects  that  a  marked  inflammatory 
reaction  would  have,  should  the  drug  be  prescribed. 

There  are  only  four  organs  in  the  body  which  need  be  considered — liver,  heart, 
kidney,  and  nervous  system. 

Liver. — The  only  late  lesion  in  which  a  reactionary  inflammation  could  do 
any  damage,  would  be  a  gumma.  Cirrhosis  is  the  result  of  a  syphilitic  infection, 
rather  than  a  sign  of  an  active  syphilitic  process,  and  only  serves  mechanically  as 
a  contraindication,  as  it  prevents  rapid  excretion  of  the  arsenic.  If  there  is  only 
one  gumma,  and  if  it  is  not  large  enough  to  have  caused  much  destruction  of  the 
hepatic  parenchyma,  an  inflammatory  reaction  would  be  innocuous.  If,  on  the 
other  hand,  much  liver  substance  had  been  destroyed,  an  inflammatory  reaction 
might  prove  fatal.  Therefore,  in  all  cases  of  gummatous  disease  of  the  liver — and 
this  applies  equally  to  the  heart  and  kidneys — it  is  better  thoroughly  to  treat  the 
case  with  mercury  and  iodides,  before  prescribing  "  606."  In  all  cases  of  acute 
yellow  atrophy,  I  think  salvarsan  should  be  given,  because  the  patient  is  bound  to 
die  if  "  606  "  is  not  given,  and  he  may  live  if  it  is.  The  reactionary  inflammation 
may  be  diminished  by  prescribing  subcutaneous  injections  of  adrenalin. 

Heart. — ^When  the  earlier  preparations  of  salvarsan  were  used,  we  had  to  contend 
with  sudden  alterations  of  blood  pressure.  With  the  preparations  now  in  use,  the 
alterations  of  blood  pressure  are  too  insignificant  to  note.  Therefore,  no  arterial 
lesion,  be  it  even  an  aneurysm  of  the  aorta,  can  be  considered  to  be  a  contra- 
indication to  neo-salvarsan.     Early  cases  of  aneurysm  are  undoubtedly  improved 


314:  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT    OF    SYPHILIS. 

by  neo-salvarsan,  and  even  in  the  late  cases,  relief  from  the  intercostal  neuralgia  is 
usually  afforded.  Myocarditis  in  the  stage  of  generalisation  is  not  a  contra- 
indication— ^indeed,  it  is  a  condition  which  urgently  calls  for  neo-salvarsan. 
Gummatous  myocarditis,  and  especially  a  gumma  in  the  bundle  of  His,  should  always 
be  energetically  treated  with  mercury  and  iodides,  before  neo-salvarsan  is  prescribed. 
In  all  late  cardiac  lesions,  there  is  a  great  probability  that  one  or  more  of  the 
coronary  arteries  is  diseased.  Endarteritis  of  the  coronary  arteries  also  accompanies 
syphilitic  aortic  disease,  and  the  slightest  reactionary  inflammation  may  be 
sufficient  to  render  the  endarteritis  momentarily  obliterative.  This  results  in 
sudden  death,  and  is  undoubtedly  the  cause  of  some  of  the  cases  of  sudden  death 
that  have  followed  the  use  of  "  606."  Rare  as  the  condition  may  be,  it  should  be 
borne  in  mind.  Pathologists  should  remember,  especially  those  who  have  to  give 
evidence  before  a  Coroner's  Court,  that  in  a  case  of  death  which  has  resulted  from 
an  inflammatory  reaction,  no  sign  of  the_  inflammatory  reaction  will  be  found  j^ost- 
mortem.  Haemorrhagic  encephalitis  and  obliterative  endarteritis  of  a  coronary  artery 
are  the  commonest  causes  of  death  after  salvarsan.  Both  are  inflammatory 
reactions.  Post-mortem,  in  the  former  case,  the  cortex  of  the  brain  may  show  no 
signs  of  a  recent  encephalitis,  and  in  the  latter  case,  the  endarteritis  of  the  artery 
in  question  may  have  ceased  to  be  obliterative.  Arsenic  is  found  in  the  liver,  and 
the  patient  has  died  of  arsenical  poisoning.  I  know  of  at  least  three  instances,  in 
which  the  verdict  given  has  been  one  of  arsenical  poisoning,  when  the  real  cause  of 
death  was  inflammatory  reaction  produced  by  the  endotoxinss  liberated  from  the 
bodies  of  the  dead  spirochaetae.  It  really  is  most  important  that  false  verdicts 
should  not  be  given  in  a  Coroner's  Court,  as  they  find  their  way  into  the  daily 
papers,  and  mislead  both  the  medical  profession  and  the  public.  AATiat  a  check  to 
patients  seeking  instant  advice  these  false  verdicts  have  alveadj  caused,  cannot 
be  appreciated,  except  by  those  who  are,  day  in  day  out,  dealing  with  venereal 
cases. 

Kidneys. — The  so-called  nephritis  of  earlj  syphilis  is,  in  over  ninety  cases  out  of 
a  hundred,  not  a  nephritis  at  all,  but  merely  an  excretion,  by  filtration  through 
the  kidneys,  of  some  of  the  protective  lipoid-globulin  or  of  the  albumin  that 
precedes  the  globulin  of  the  serum.  Therefore  salvarsan  is  urgently  called  for. 
In  late  cases  of  syphilis,  nephritis  secondary  to  arterial  trouble,  "  606  "  is  contra- 
indicated,  not  because  there  is  any  fear  of  sudden  death  occurring,  but  because 
the  arsenic  cannot  be  properly  eliminated.  Storing  up  of  the  arsenic  can  only  lead 
to  dangerous  symptoms,  should  several  injections  be  given,  and  as  has  been  my 
experience,  in  cases  of  late  syphilitic  nephritis,  the  patients  have  borne  the  first 
two  injections  so  badly,  that  one  would  not  dream  of  repeating  them.     As  one 


TOXIC    SYMPTOMS    OF    SALVARSAN    AND    NEO-SALVARSAN.  315 

alvrays  starts  with  small  quantities  of  the  drug,  little  damage  can  be  caused,  as  the 
case  is  never  so  bad  that  elimination  is  totally  impossible. 

Nervous  System. — Inflammatory  reaction  in  the  nervous  S3^stem  is  by  far  the 
commonest  cause  of  death  after  salvarsan.  Death  may  occur  in  early  S3'philis  or 
in  late  syphilis.  If  in  the  former,  the  probability  is  that  it  is  a  case  of  haemorrhagic 
encephalitis,  if  in  the  latter,  a  case  of  degenerative  encephalitis. 

As  to  how  and  when  haemorrhagic  encephalitis  arises,  the  reader  must  be  referred 
to  Chapter  XXIII,  where  the  whole  matter  is  discussed  in  detail.  Suffice  it  here  to 
state  that,  in  all  cases  of  generalised  syphilis,  in  which  no  treatment  has  been  given, 
and  "  606  "  is  contemplated,  the  possibility  of  setting  up  a  haemorrhagic  encephalitis 
should  be  borne  in  mind,  because,  in  every  instance,  it  can  be  prevented.  There 
are  three  ways  of  preventing  haemorrhagic  encephalitis,  and  tliese  will  now  be 
enumerated  : — 

(1)  Killing  off  all  the  spirochaetae  first,  with  mercury.  In  other  words,  use 
mercury  until  all  the  symptoms  have  vanished,  and  then  begin  the  "  606." 

(2)  Begin  with  "  606,"  or,  better,  with  "  914,"  in  small  doses,  and  repeat 
them  in  gradually  increasing  doses,  allowing  the  shortest  possible  interval  to  elapse 
between  each  injection. 

(3)  If  the  treatment  is  begun  with  neo-salvarsan,  give  subcutaneous  injections 
of  adrenalin,  during  the  second  and  third  days  after  the  first  three  injections. 

I  feel  myself,  that  much  valuable  time  is  lost  by  giving  mercury  first ;  and 
if  the  patient  has  noticeable  skin  lesions,  he  is  naturally  most  anxious  to  undergo 
that  form  of  treatment  which  will  get  rid  of  them  most  rapidly.  Moreover,  giving 
mercury  first,  increases  the  toxicity  of  the  arsenical  compounds. 

If  one  decides  to  commence  the  treatment  with  neo-salvarsan.  the  risk  of 
haemorrhagic  encephalitis  arising  is  nil,  if  seven  to  nine  injections,  beginning  with 
0'4.5  grm.,  are  injected  intravenously  every  third  or  fourth  day,  anyhow  for  the  first 
five  injections.  The  other  injections  can  be  given  at  weekly  intervals,  if  desired. 
Adrenalin  is  an  additional  safeguard,  and  if  it  be  prescribed,  even  when  symptoms 
of  haemorrhagic  encephalitis  have  already  started,  the  chances  are  that  the  patient 
will  be  saved. 

When  "  606  "  first  came  in,  I  had  one  death  from  haemorrhagic  encephalitis, 
but  I  have  never  seen  a  symptom  of  this  condition  since.  If  our  knowledge  had 
been  as  great  then  as  it  is  now,  there  is  no  doubt  that  this  case  would  have  been 
saved. 

Case  27. — On  the  third  day  after  the  second  injection  of  "  606,"  the  patient,  after 
having  previously  complained  of  bad  headache,  developed  Jacksonian  epilepsy, 
which  rapidly  developed  into  Status  epilepticus,  in  which  condition  the  patient  died. 


316  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

The  patient  was  in  the  generalisation  stage.  He  had  a  severe  papular  rash,  and 
an  iritis  of  the  right  eye.  The  first  injection  of  "  606  "  {0"6  gnn.)  had  been  given 
a  week  previously,  without  symptoms  other  than  those  which  followed  every 
injection  in  those  days,  when  no  attention  was  paid  to  the  purity  of  the  water.  The 
second  injection  was  also  0'6  grm. 

Posl-mortem,  the  patient  had  a  subarachnoid  cyst  over  the  Kolandic  area,  on 
the  side  opposite  to  that  in  which  the  Jacksonian  epilepsy  started.  This  was  of  old 
duration,  and  was  probably  produced  by  an  accident  some  years  before ;  never- 
theless, it  would  appear  to  have  been  a  locus  minor  resistentiae.  A  microscopic 
examination  showed  a  degeneration  of  the  nerve  cells  around  and  underneath  the 
cyst,  but  nothing  else.  At  that  time,  the  nerve  degeneration  would  have  been 
pronounced  as  being  typical  of  arsenical  intoxication.  One  now  knows  that  it  is 
due  to  the  endotoxine  liberated  by  the  dead  spirochaetae.  In  this  case,  as  in  all, 
the  vascular  dilatation  had  vanished  post-mortem.  In  cases  of  haemorrhagic 
encephalitis,  it  is  useless  either  to  trephine  or  to  do  a  lumbar  puncture. 

In  the  late  degenerative  cases,  death  is  due  to  a  liberation  of  spirochaetal 
endotoxine,  which  does  not  amount  exactly  to  an  inflammatory  reaction.  Death, 
as  a  rule,  occurs  later  than  in  the  early  haemorrhagic  encephalitis,  for  reasons  which 
will  now  be  made  clear. 

In  degenerative  encephalitis  (G.P.I.),  owing  to  the  pabulum  upon  which  the 
organisms  are  nourished,  the  extracellular  development  of  the  male  phase  of  the 
Leucocytozoon  syphilidis  is  much  in  evidence,  with  the  result  that  the  lesions  are 
rich  in  spirochaetae. 

Owing  to  the  fact  that  the  spirochaetae  are  not  in  the  walls  of  the  blood-vessels, 
as  in  haemorrhagic  encephalitis,  but  are  extramurally  situated,  it  will  follow  that 
only  a  few  will  be  killed  at  a  time,  as  only  a  trace  of  the  drug  will  reach  the  spot 
in  which  they  are.  Under  these  circumstances,  the  amount  of  endotoxine  resulting 
from  the  death  of  only  a  few  spirochaetae  will  be  very  small  in  amount,  consequently, 
the  inflammatory  reaction  will  never  be  severe  or  acute  enough  to  cause  damage 
of  its  own  accord.  As  the  nerve  cells  in  degenerative  encephalitis  are  apt' to  be 
on  their  last  legs,  the  gradual  accumulation  of  endotoxine,  from  the  gradual  process 
of  destruction  of  the  spirochaetae,  is  just  sufficient  to  knock  the  cells  clean  out,  and 
kill  the  patient. 

Although  death  may  result  in  cases  of  degenerative  encephalitis,  after  the 
first  and  after  the  second  injection  of  salvarsan,  it  is  more  usual  for  death  to  occur 
much  later,  and  for  the  patient  to  die  with  symptoms  of  aggravation  of  the  trouble. 
Salvarsan  and  neo-salvarsan  cannot  be  said  to  cause  death  directly  in  cases  of 
degenerative  encephalitis,  but  they  certainly  do,  in  the  majority  of  the  cases,  make 


TOXIC    SYMPTOMS    OF   SALVARSAN    AND    NEO-SALVARSAN.  317 

the  patient  very  mucb.  worse,  so  that  he  dies  sooner  than  he  would  have  done  if  he 
had  been  left  alone. 

In  the  ameningeal  form  of  degenerative  encephalitis,  death  after  salvarsan  is 
always  due  to  an  aggravation  of  the  symptoms  of  the  disease,  but  in  the  meningeal 
form,  death  may  be  sudden,  and  due  to  a  true  inflammatory  reaction,  because  the 
spirochaetae  are  more  in  contact  with  the  vessels,  more  are  killed,  and  more  of  the 
drug  can  get  to  them. 

Although  I  have  never  had  a  sudden  death  in  a  case  of  degenerative  encephalitis 
myself,  I  have  had  six  cases  in  which  the  patient  was  made  very  much  worse,  and 
died  sooner  than  he  otherwise  would  have  done.  I  know  of  four  other- cases,  in 
which  I  was  personally  interested,  which  came  to  an  untimely  end.  In  two  of  these 
the  patient  committed  suicide — one  on  the  third  day  after  the  first  injection,  and 
the  other  one  week  after  the  second.  Oddly  enough,  both  of  these  cases  were  in 
the  quiescent  period  when  '  606  "  was  prescribed.  In  one  case  the  man  had  been 
"perfectly  well  "  for  two  years,  and  in  the  other  case  for  nine  months  only.  Both 
had  had  only  one  attack  before. 

From  the  experience  I  have  had,  I  have  now  made  up  my  mind  to  withhold 
salvarsan  and  neo-salvarsan  in  cases  of  degenerative  encephalitis,  and  I  would  warn 
others  never  to  put  under  treatment  a  patient  who  has  had  an  attack,  but  is  now 
in  the  quiescent  stage. 

We  can  now  pass  on  to  nervous  lesions,  which  are  to  be  met  with  between 
the  early  haemorrhagic  encephalitis  and  the  late  degenerative  encephalitis.  These 
are  cases  of  either  pure  intracranial  meningitis,  or  cases  in  which  the  nerve  tissue 
underneath  has  become  involved — meningo-encephalitis — but  in  which  the 
encephalitis  is  not  of  the  tj^ical  degenerative  type. 

It  might  here  be  stated,  that  no  cord  lesion  is  an  absolute  contraindication  to 
"  606,"  and  that  the  question  of  salvarsan  in  these  cases  will  be  fully  gone  into  in 
Chapter  XXIX. 

Inflammatory  reaction  in  a  case  of  widespread  pachymeningitis  may,  owing 
to  the  rise  of  intracranial  pressure  produced  thereby,  render  the  patient  uncon- 
scious. I  have  had  three  cases  under  my  own  observation.  In  two,  the  patient 
became  suddenly  unconscious  on  the  third  day  after  the  third  injection,  and  in  the 
third,  on  the  same  day  after  the  second  injection.  Lumbar  puncture  produced 
immediate  relief  in  one  of  the  cases,  and  the  relief  was  maintained,  while  in  the  other 
two,  the  operation  made  no  appreciable  difference.  In  none  did  the  symptoms 
recur  after  the  subsequent  injections,  as  each  patient  had  six  more.  I  had  another 
case,  in  which  the  patient  had  a  severe  syphilitic  basal  meningitis,  and  he  died 
of  asphyxia,  produced  by  a  rise  of  intracranial  pressure,  due  to  a  severe  reactionary 


318  THE  bioi-oc:y,  clinical  aspect  and  treatment  of  syphilis. 

inflammation  after  too  large  a  second  injection  of  "  606,"  and  after  too  long  an 
interval  had  been  allowed  to  elapse  between  the  two  injections.  This  death  occurred 
early  in  1910,  before  our  knowledge  was  as  complete  as  it  is  now.  Death  would  not 
have  occurred,  if  the  patient  had  received  several  intravenous  injections  of  neo- 
salvarsan  at  short  intervals,  and  if  a  lumbar  puncture  had  been  performed  at  the 
moment  when  signs  of  a  rise  of  intracranial  blood  pressure  had  shown  themselves. 

If  an  inflammatory  reaction  occurs  in  cases  of  meningo-encephalitis,  and  the 
patient  gets  an  aggravation  of  his  symptoms,  on  no  account  whatever  should 
treatment  be  suspended,  as  the  ultimate  condition  of  the  patient  may  be  worse 
than  the  first.  The  thing  to  do,  is  to  push  the  treatment  as  quickly  as  possible, 
and  instead  of  relying  only  upon  intravenous  injections,  to  give  intraspinal  injec- 
tions of  salvarsanised  serum  as  well. 

The  following  case  will  show  the  importance  of  continuing  the  treatment : — 

Case  48. — Patient,  a  man  aged  29,  had  no  history  of  a  sore,  but  had  had  a  bad 
throat  in  1911,  which  was  diagnosed  as  sj'philis.  The  patient  was  treated  with  mercury 
internally  until  January,  1914,  when  he  developed  a  rash  (?  nature).  At  this  time 
he  was  also  said  to  have  had  a  left  hemiplegia,  which  came  on  qiiite  suddenly,  but 
the  attack  had  not  been  preceded  by  headaches.  As  far  as  I  could  gather  from  the 
patient,  when  I  saw  him  in  September,  1914,  he  completely  recovered  from  the 
hemiplegia  in  a  few  days,  and  had  had  no  treatment  since.  On  examination,  I 
found  that  the  pupils  were  unequal  R  >  L.  The  reflexes  of  the  R.  j^upil  were 
not  as  brisk  as  those  of  the  L.  pupil,  and  in  both  eyes  the  reflexes  were  diminished. 
All  the  other  reflexes  were  very  brisk  indeed,  but  not  more  so  on  the  right  side  than 
the  left.  There  was  bilateral  ankle  clonus,  and  an  extensor  response  on  both  sides. 
Sensations  were  unaltered.  Patient  answered  questions  correctly  and  quickly, 
and  beyond  feeling  as  he  called  it,  "nervous,"  he  had  no  symptoms  to  complain  of. 

Examination  of  the  Blood. — Wassermann  reaction    +  +. 

Examination  of  the  Cerebrospinal  Fluid. — Pressure  not  raised.  Fluid  clear. 
Strong  positive  lymphocytosis.  Strong  positive  Nonne-Apelt  reaction.  Excess  of 
albumin  and  globuhn.     Wassermann  reaction  100  per  cent.  (1  10  c.c.)   +  +  -f-. 

Patient  was  admitted  into  the  Lock  Hospital  and  received  two  intravenous 
injections  of  "  606."  On  the  third  day  after  the  second  injection,  the  patient  went 
off  his  head — ^he  talked  the  most  utter  nonsense,  took  his  discharge,  and  found 
his  way  home.  Two  days  later,  the  patient  was  brought  to  see  me.  He  stood 
staring,  took  several  minutes  to  answer  a  question,  and  then  could  only  answer  it 
correctly  if  it  were  a  simple  one,  such  as  asking  him  his  name,  age,  etc.  His  reflexes 
had  become  brisker  than  ever.  I  then  gave  him  another  intravenous  injection  of 
salvarsan  and  an  intrathecal  injection  of  salvarsanised  serum  the  next  day,  with  the 


TOXIC    SYMPTOMS    OF   SALVARSAN   AND    NEO-SALVARSAN.  319 

result,  that  in  three  days'  time  the  patient  was  absolutely  normal  again.      Further 
intrathecal  treatment  was  given. 

If  care  is  given  to  the  points  I  have  mentioned  in  this  chapter,  and  if  only  the 
purest  distilled  water  is  used,  the  administration  of  neo-salvarsan  is  absolutely 
unaccompanied  by  the  smallest  risk.  I  have  given  several  thousands  of  injections, 
and  have  never  experienced  any  evil  effects  other  than  those  I  have  been  most 
careful  now  to  mention,  and  all  the  evil  effects  I  have  experienced  happened  before 
the  end  of  the  year  1912. 

Although,  injection  for  injection,  neo-salvarsan  is  not  as  potent  as  salvarsan, 
I  always  prefer  to  use  the  former,  becaiise  the  inflammatory  reaction  is  never  so 
severe  as  in  the  case  of  the  latter,  and  quite  as  good  results  are  obtained  with 
neo-salvarsan  as  with  salvarsan,  provided  sufficient  injections  are  given.  As  it  is 
now  necessary  to  give  several  injections,  and  at  the  shortest  intervals,  in  the  end 
better  results  can  be  obtained  with  neo-salvarsan  than  with  salvarsan,  because  not  only 
is  the  inflammatory  reaction  sUghter  and  the  observer  not  frightened  away  from 
giving  further  injections,  but  the  ordinary  after-efEects  are  nothing  after  neo-salvarsan, 
and  practically  never  does  a  patient  show  an  idiosyncrasy  to  the  drug.  In  the  case 
of  salvarsan  there  is  always  the  additional  factor  of  the  sodium  hydrate  used  for 
neutralising  purposes,  for  it  may  so  often  give  rise  to  symptoms  which  make  one 
hesitate  to  repeat  the  injection,  or,  at  the  least,  compel  one  to  allow  a  longer 
interval  than  is  desirable,  to  elapse  between  the  injections.  Before  closing  this 
chapter,  mention  might  be  made  of  the  question  of  treating  patients  with  neo-salvarsan 
as  out-patients. 

There  are  two  alternatives — either  that  the  patient  should  be  kept  in  after 
an  injection,  or  allowed  to  go  out  at  once.  If  the  patient  is  to  be  an  in-patient, 
there  can  be  no  reason  to  detain  him,  other  than  to  have  ready  access  to  him  should 
the  inflammatory  reaction  cause  symptoms  which  require  urgent  treatment.  Now, 
as  the  symptoms  following  an  inflammatory  reaction  do  not,  as  a  rule,  appear  till 
the  third  day,  it  will  at  once  be  seen  how  senseless  it  is  to  detain  a  patient  for  any 
period  shorter  than  this. 

Patients  who  are  in  the  best  of  health,  and  in  whoni  the  injection  makes  no 
difference,  severely  resent  being  detained  for  three  or  more  days,  especially  if  the 
process  has  to  be  repeated.  Patients,  moreover,  resent  going  to  nursing  homes 
for  "  606  "  treatment,  for  obvious  reasons.  As  the  reactionary  inflammation  is,  as 
has  already  been  stated,  so  slight  after  neo-salvarsan,  if  this  drug  is  used,  patients 
can  leave  immediately  and  go  to  their  destination,  even  by  train  if  necessar}'.  This 
has  been  my  practise  for  three  years,  and  I  have  never  had  cause  to  find  fault 
with  it. 


320  THE   BIOLOGY,    CLINICAL    ASPECT   AND   TREATMENT   OF   SYPHILIS. 

In  cases  with  nervous  lesions,  in  which  an  inflammatory  reaction  is  to  be 
feared,  the  patient  can  be  treated  as  an  in-patient  for  the  second  and  third  injec- 
tions, if  thought  necessary. 

'  Wechselmann  (1911),  "  Deutsch.  nied.  Woch.,"  xxxvii,  778. 

-  Yakimofi  (1911),  "  Miinoh.  med.  Woch.,"  Iviii,  2601. 

'  Ibid.  (1912),  lis,  124. 

*  Aladow  (1911),  "  Charkowsky  Medizinsky  Joiirii.,"  xi,  5. 

°  Milian  (1914),  "  Bull,  de  la  Soc.  Franc,  de  Derm,  et  de  Syph.,"  xxv,  231. 

'  Igersheimer  (1912),  "  Zeitschr.  f  Chemotherapie,"  i,  106. 


CHAPTER  XXIX. 

THE  TREATMENT   OF  SYPHILIS.        ■    ^ 

For  the  sake  of  lucidity,  sjq^hilis  will  be  divided  into  the  following  stages,  and 
the  treatment  of  each  will  be  considered  separately  :  (a)  Stage  of  the  initial  lesion  ; 
(b)  Stage  of  the  generalisation  of  the  virus ;  (c)  Recurrent  stage  ;  (d)  Latent 
stage  ;  (e)  Syphilis  in  women  ;  (/)  Congenital  syphilis  ;  (g)  Syphilis  of  the  nervoua 
system. 

Primary  Sore. 

Excision  of  the  primary  sore  should  be  practised,  when  possible.  When 
impossible,  owing  to  the  site  affected,  it  should  be  cauterised,  or,  failing  cauterisa- 
tion, mercurial  ointment  should  be  rubbed  in,  until  every  trace  of  the  induration 
has  vanished. 

Induration  often  prevents  sterilisation  of  the  site  of  the  initial  lesion,  and 
since  salvarsan  quickly  gives  the  clue  to  the  host  that  there  is  no  necessity  for  a 
further  continuation  of  the  production  of  antibodies,  the  host  is  unaware  that  it 
has  any  spores  locked  iip  in  what  was  the  chancre.  Should  the  activity  of  these 
spores  reawaken,  a  lesion  will  be  produced,  indistinguishable  from  a  primary  sore. 
Should  such  a  sore  occur  in  any  position  other  than  in  the  site  of  the  original 
chancre,  the  case  is  considered  to  be  one  of  reinfection.  Is  it  not  possible  that  the 
majority  of  these  cases  of  so-called  reinfection  are  really  cases  of  auto-reinfection  ? 
If  sufficient  treatment  be  given,  and  if  it  be  prescribed  early  enough  in  the  disease, 
to  give  the  host  the  signal  that  no  further  antibodies  are  required,  it  does  not  mean 
that  all  the  spores  have  been  killed.  A  few  may  be  hidden  in  any  part  of  the  body. 
Now,  should  these  develop,  owing  to  the  fact  that  the  production  of  antibodies  was 
so  quickly  checked,  the  host  wiU  behave  to  these  spores  as  would  a  fresh  host  which 
had  never  had  syphilis,  with  the  result  that  the  lesion  will  be  clinically  a  chancre, 
and  not  a  recurrent  papule.  To  give  an  instance.  I  had  a  case,  very  early  in  the 
generalisation  stage,  which  I  had  treated  with  salvarsan  and  mercury.  Some  months 
later,  the  patient  came  to  me  with  a  sore  on  his  chin;    clinically,  it  was  a  typical 

x2 


322  THE   BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OP   SYPHILIS. 

chancre,  accompanied  by  the  usual  adenitis,  etc.  I  have  had  another  similar  case, 
in  which  a  sore  simulating  a  cliancre  appeared  on  the  nape  of  the  neck.  Had  these 
two  sores  appeared  on  the  penis,  they  might  have  been  mistaken  for  cases  of 
reinfection.  I  have  seen  seven  cases  with  a  recurrent  sore  on  the  penis,  in  a 
different  position  from  the  original  sore,  therefore  a  chancre  redux  could  be  excluded, 
and  five  of  those  I  was  convinced  were  cases  of  auto-reinfection.  In  reading  the 
literature,  I  have  noticed  that  the  greater  number  of  cases  of  reinfection  occurred 
some  time  ago,  not  recently,  i.e.,  not  since  the  continuous  treatment  mth  salvarsan 
has  been  in  vogue,  a  point  in  favour  of  the  auto-reinfection  view.  V  Before  the 
salvarsan  era,  -f'had  seen  three  cases^of  auto-reinfection,  ©ne~of-wnieh:  I  showed 
before  the  Dermatological  Section ;i  ajid  since  I  have  made  it  a  rule  to  give  several 
injections  of  salvarsan:  at  the  shortest  possible  intervals,  and  to  supplement  these 
with  thorough  courses  of  mercury ^^  have  not  seen  a  single  case  of  auto-reinfection. 

The  question  as  to  the  advisability  of  removing  the  lymphatic  glands  draining 
a  primary  sore  has  frequentlj'  arisen,  and  their  excision  is  even  practised  by  some. 

Those  in  favour  of  removal  state  that  it  is  only  necessary  to  excise  the  glands 
which  are  eidarged. 

Those  cases  in  which  the  lymphatic  glands  are  most  enlarged  are  usually  those 
in  which  the  infection  is  slight,  and  histological  examination  reveals  the  smallest 
number  of  parasites.  Those  cases  in  which  the  lymphatic  glands  are  smallest  and 
hardest,  are  usually  those  in  which  the  infection  is  severe,  and  a  histological  examina- 
tion reveals  the  largest  number  of  parasites.  Therefore  a  ratio  exists  between  the 
size  of  the  glands  and  the  protective  capacity  of  the  host  against  the  disease. 

Since  the  lymphatic  glands  are  responsible  for  some  of  the  protective  substances 
with  which  the  host  attacks  the  parasite,  it  would  appear  wiser  to  leave  them  alone. 

Having  treated  the  sore  locally,  I  give' from  five  to  seven  intravenous  injections 
of  neo-salvarsan,  with  two,  three  or  four  days'  interval  between  each.  To  be  quite 
sure  that  the  organism  has  not  become  generalised,  I  examine\  the  cerebro-spinal 
fluid,  and  close  the  treatment  with  one  year's  mercury,  given  in  three  courses  of 
eight  weekly  intramuscular  injections  of  grey  oil,  allowing  two  months  to  intervene 
between  each  course,  for  the  first  three  weeks  of  which  iodides  are  prescribed 
internally.  ^ 

Tabulated,  the  treatment  appears  as  follows  : — 

1.  Local  treatment. 

2.  Intravenous  injection  of  neo-salvarsan,  O'iS  grm. 

3.  Four  days  later,  second  injection  of  neo-salvarsan,  0"J:.5  grm. 

4.  Four  days  later,  third  injection  of  neo-salvarsan,  0'45  grm. 

5.  Four  days  later,  fourth  injection  of  neo-salvarsan,  0"60  grm. 


THE   TREATMENT   OF    SYPHILIS.  323 

G.  Four  days  later,  fifth  injection  of  neo-salvarsan,  0'60  grm. 

7.  Four  days  later,  sixth  injection  of  neo-salvarsan,  0"60  grm. 

8.  A  week  later,  seventh  injection  of  neo-salvarsan,  0"75  grm. 

9.  A  week   later,   an  intramuscular  injection   of  grey  oil,   which    should    be 

continued  weekly  for  eight  weeks. 

10.  Iodides  for  three  weeks. 

11.  No  treatment  for  five  weeks. 

12.  Mercury,  iodides,  and  rest  as  before,  twice  repeated. 

Stage  of  Generalisation. 

A  good  plan  is  to  examine  the  cerebro-spinal  fluid  before  treatment  is  com- 
menced. If  the  fluid  is  normal,  I^ve  seven  injections  ot  neo-salvarsan^  at  four  to 
seven  days'  interval.  If  the  fluid  shows  pathological  changes, -Lgis^B  nine  to  eleven 
injections  ;  and  if  still  positive  after  this,  I  give  as  many  intrathecal  injections 
of  salvarsanised  serum  as  are  necessary'  to  render  the  fluid  normal  again.  Then 
six  courses  of  mercurial  treatment  are  prescribed,  and  spread  out  over  two  years, 
with  the  iodides  as  above. 

Tabulated,  the  treatment  appears  as  follows  : — 

1.  (2-4)  as  above. 

2.  Four  days  later,  fourth  injection  of  neo-salvarsan,  0"4.5  grm. 

3.  Four  days  later,  fifth  injection  of  neo-salvarsan,  0'4.5  grm. 

4.  Four  days  later,  sixth  injection  of  neo-salvarsan,  0'60  grm. 

5.  Four  to  seven  days  later,  seventh  injection  of  neo-salvarsan,  0"G0  grm. 

6.  Seven  days  later,  eighth  injection  of  neo-salvarsan,  0'60  grm. 

7.  Seven  days  later,  ninth  injection  of  neo-salvarsan,  0"75  grm. 

8.  Seven  days  later,  tenth  injection  of  neo-salvarsan,  0"75  grm. 

9.  Seven  days  later,  eleventh  injection  of  neo-salvarsan,  0  -90  grm. 

10.  Mercury,  iodides  and  rest,  as  above,  to  be  repeated  six  times. 

Recurrent  Stage. 

If  the  recurrence  is  early,  and  if  the  previous  treatment  has  been  poor,  then 
the  case  should  be  treated  as  belonging  to  the  stage  just  described.  If,  on  the 
other  hand,  the  recurrence  is  late,  and  the  previous  treatment  has  been  good  or 
poor,  three  facts  should  be  considered  before  any  line  of  treatment  is  adopted — 
site  of  recurrence,  marriage,  age  of  patient. 

If  the  site  is  in  or  near  a  vital  organ,  and  if  any  spread  or  future  recurrence 
would  endanger  the  life  or  blight  the  happiness  of  the  patient,  he  should  receive 


324  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

the  same  treatment  as  previously  mentioned.  A  man  who  is  going  to  marry 
should  be  treated  likewise,  but  marriage  need  not  necessarily  be  delayed  for  two 
years.  If  the  site  is  not  an  important  one,  and  if  the  patient  is  not  going  to  marry, 
and  if  he  is  of  a  certain  age,  his  treatment  should  be  symptomatic,  i.e.,  two  to  three 
injections  of  salvarsan  and  a  course  or  two  of  mercury. 

Latent  Stage. 

Wlien  one  relied  solely  upon  the  Wassermann  reaction  in  this  stage,  treating 
those  who  gave  a  positive  reaction,  and  leaving  those  who  gave  a  negative  reaction, 
the  course  was  clear ;  but  now  that  I  no  longer  attach  the  importance  to  the 
reaction  which  I  once  did,  I  have  had  perforce  to  alter  my  routine.  ( In  this  stage, 
I  now  begin  by-  examining  the  cerebro-spinal  fluid.'?  If  tlie  cerebro-spinal  fluid  is 
normal,  however  positive  the  blood  may  be,  -I— do-  not -advise  any  treatment. 
Naturally,  the  kind  of  treatment  the  patient  has  had  before,  and  the  interval  that 
has  elapsed  since  the  infection,  are  points  which  have  to  be  taken  into  consideration. 
If  the  cerebro-spinal  fluid  is  positive,  whether  the  blood  is  positive  or  negative, 
i-give  as  many  injections  of  salvarsanised  serum  intrathecally?  as  are  necessary 
to  render  the  fluid  normal  again,  and  supplement  these  by  one  or  two  j^ears' 
treatment  with  mercurv. 

Syphilis  in  Women. 

Since  syphilis  in  women  is  the  worst  of  the  evils  caused  by  syphilis,  I  must 
repeat  a  few  lines  that  have  already  appeared  in  Chapter  XXV. 

Syphilis  in  women  may  be  looked  upon  as  the  greatest  curse  of  the  disease, 
since  a  woman  who  has  once  conceived  a  syphilitic  infant,  may  infect,  in  utero,  all 
her  subsequent  offspring,  although  the  father  of  the  latter  may  be  a  different 
husband,  who  has  never  had  the  disease. 

To  make  matters  worse,  conceptional  syphilis  is  not  recognised  until  the  infant 
has  been  seen  to  settle  the  diagnosis,  owing  to  the  fact  that  many  mothers  shc\v  no 
evidence  of  the  disease  until  after  the  child-bearing  period  is  over,  and,  as  often 
as  not,  the  Wassermann  reaction  during  this  period  is  negative. 

A  general  rule  may  be  formulated,  viz.,  that  if  a  woman  contracts  syphilis 
after  she  has  conceived,  the  Wassermann  reaction  will  be  positive,  because  the 
disease  becomes  generalised  arjd  behaves  in  the  ordinary  way ;  that  if  a  woman 
contracts  syphilis  at  the  time  of  conception,  the  Wassermann  reaction  will  often 
be  negative,  because  the  disease  does  not  become  generalised,  at  any  rate  not  until 
some  later  date. 


»AM^^^'^ 


THE   TREATMENT   OP   SYPHILIS.  325 

Herein  we  have  the  explanation  why  sucli  patients  develop  manifestations  only 
after  the  child-bearing  period  is  over,  and  why  it  so  frequently  happens  that  the 
first  and  last  pregnancies  result  disastrously,  while  one  or  more  healthy  children 
may  be  born  in  the  interim.  It  is  interesting  to  inquire  into  the  rationale  of 
conceptional  syphilis. 

The  germ  must,  in  the  first  instance,  be  conveyed  by  the  semen.  But  does 
the  germ,  which  is  with  the  embryo  in  the  uterus,  develop  after  a  time  into  the 
gamete  forms  described  by  me — which  I  regard  as  responsible  for  the  symptoms — 
at  the  expense  of  the  embryo,  with,  maybe,  its  death,  and  leave  some  of  the 
sporozoites  behind  after  its  expulsion,  to  be  already  there  to  develop  at  the  expense 
of  the  next  embryo?  Or,  does  the  mother  get  infected  directly,  but  the  symptoms 
are  prevented  from  recurring,  owing  to  the  formation  of  some  chemical  substance, 
possibly  in  the  form  of  a  lipoid  from  the  embryo,  which  prevents  the  gametes  from 
being  developed  ? 

When  the  question  was  discussed,  after  the  Spirochaeta  pallida  had  been 
discovered,  when  the  Spirochaeta  pallida  was  held  to  be  responsible  for  everything 
syphilitic,  only  confusion  resulted.  If  my  discovery  of  the  Leucocytozoon  sy2}hilidis 
be  accepted,  and  the  views  accepted  that  the  sporozoite  is  the  infective  agent,  and 
that  the  gametes  are  responsible  for  the  symptoms,  the  alternative  need  not  appear 
in  the  above  illustration,  as  both,  in  part,  may  turn  out  to  be  correct. 

It  may  be  considered  that  the  sporozoites,  themselves  inert,  travel  in  the 
semen,  reach  the  uterus,  and  find  themselves  in  both  the  maternal  and  foetal 
portions  of  the  embryo.  Those  in  the  foetal  portion,  after  a  period  of  some  weeks, 
develop  into  gametes,  which  may  or  may  not  kill  the  embryo. 

Those  in  the  maternal  portion  find  themselves  unable  to  develop,  owing  to  a 
chemical  substance,  from  the  chorionic  cells,  which  circidates  in  the  mother's  blood, 
but  not  in  the  foetal,  and  so  they  remain  dormant  for  a  time.  Herein  lies  the 
solution  of  the  phenomenon  that  a  mother  may  give  birth  to  an  actively  syphilitic 
infant,  without  herself  giving  even  so  much  as  a  positive  Wassermann  reaction. 

The  theory  above  put  forward,  will  also  explain  the  fact  that  a  woman  who  has 
once  given  birth  to  a  syphilitic  child  is  always  liable  to  do  so  again,  although  the 
father  of  her  later  children  may  be  another  husband  who  has  himself  never  suffered 
from  the  disease. 

Hence  the  necessity  for  treating  such  a  case  throughout  the  whole  period  of 
each  succeeding  pregnancy. 

To  women  who  are  syphilitic,  I  give,  as  soon  after  they  have  conceived  as 
possible,  six  intravenous  injections  of  neo-salvarsan,  and  1  continue  the  treatment 
with  mercury,  till  as  near  the  time  the  child  is  to  be  born  as  can  be  done. 


326  the  biology,  clinical  aspect  and  treatment  of  syphilis. 

Congenital  Syphilis. 

Attempts  have  been  made  to  limit  the  use  of  mercury  to  those  manifestations 
which  correspond  to  the  so-called  secondary  in  the  acquired  form,  and  potassium 
iodide  to  those  simulating  the  so-called  tertiary  symptoms.  But  if  the  child  has 
s}T3hilitic  symptoms  of  any  nature  whatever,  this  is  evidence  of  an  active  vims ; 
therefore  mercury  should  be  invariably  employed. 

Potassium  iodide  is  undoubtedly  useful  in  the  late  manifestations,  but  should 
never  be  solely  relied  up)n. 

Mercury  is  best  given  intermittently,  each  course  being  followed  by  iodides. 
Iodides,  given  in  this  way,  aid  elimination  of  the  superfluous  mercury  which  has 
been  stored  up  in  the  system.  Infants  are  very  tolerant  of  mercury  given  inter- 
nally, because  they  are  toothless  and  consequently  run  no  risk  of  stomatitis. 

Treatment  should  be  commenced  as  soon  as  the  case  is  diagnosed. 

Half  a  grain  of  grey  powder  should  be  given  in  milk  three  times  a  day;  if 
there  is  any  diarrhoea,  gr.  iii  of  pulv.  cretce.  aromat  may  be  added.  After  nine  months 
of  age,  the  dose  should,  by  gradual  increase,  be  doubled.  This  treatment  should 
be  continued  for  three  years,  and  then  be  followed  by  5-10  m.  of  syrupusferri  iodidi 
three  times  a  day,  for  three  weeks.  If  symptoms  have  not  disappeared  before  the 
iodide  is  started,  or  if  ib  is  advisable  to  get  the  child  quickly  under  the  influence 
of  mercury — for  instance,  in  cases  of  epiphysitis,  iritis,  etc. — the  internal  treat- 
ment should  be  augmented  by  inunctions,  10-20  gr.  of  ung.  hydrarg.  being  nibbed 
in  gently  for  about  an  hour  every  other  night,  a  fresh, site  being  chosen  for  each 
application.  The  rubbing  should  be  performed  either  in  the  early  morning  or  in 
the  evening  ;  the  part  is  then  to  be  well  covered  with  a  flannel  binder,  and  the 
ointment  washed  off  at  the  next  bath  time. 

Infants  are  especially  liable  to  dermatitis ;  therefore  it  is  important  never  to 
allow  any  of  the  ointment  to  get  near  the  groins,  where  the  urine  acts  as  an 
additional  irritating  factor.  Should  dermatitis  ensue,  inunctions  must  be  stopped 
and  recourse  had  to  injections.  AVhile  injections  are  being  used,  the  oral  adminis- 
tration must  be  stopped. 

Intramuscular  injection  into  the  glutei  of  a  10  per  cent,  emulsion  of  mercury 
salicylate,  in  liquid  paraffin  or  almond  oil,  is  the  best.  The  injection,  3  m.,  shoixld 
be  given  twice  a  week  for  six  weeks,  or  until  symptoms  have  disappeared  ;  iodides 
should  then  be  exhibited. 

If  the  child  has  open  sores,  nothing  is  so  efficacious  as  a  mercurial  bath, 
containing  20  gr.  of  the  perchloride  in  3  gallons,  continued  daily  until  the  sores 
have  healed. 


THE   TREATMENT   OF   SYPHILIS.  327 

Application  of  emplastrum  cinereum,  or  wearing  next  to  tlie  slcin  clotlies 
impregnated  with  mercury,  is  a  useful  adjunct  in  treatment,  if  neither  of  the  above 
forms  can  be  borne. 

After  the  first  year,  the  treatment  should  be  intermittent,  i.e.,  one  of  the 
above  methods  should  be  em  pi  03' ed  for  six  weeks,  or  until  symptoms  have  dis- 
appeared, and  then  followed  by  iodides.  This  course  should  be  repeated  three 
times  a  year,  for  the  ensuing  two  years. 

Congenital  syphilis,  with  late  manifestations,  should  be  treated,  by  preference, 
with  inunctions  or  injections  of  mercury. 

We  come  now  to  discuss  the  value  of  the  new  arsenic  preparations  in  congenital 
syphihs.  If  a  child  is  born  with  symptoms,  the  chances  are  that  it  will  die. 
Salvarsan,  or  neo-salvarsan,  given  intramuscularly,  may  save  it,  but,  in  my  experience, 
this  treatment  may  also  hasten  the  fatal  termination  ;  indeed  the  risk  of  its  so 
doing  is  great.  Although  giving  the  mother  an  intravenous  injection  of  salvarsan, 
and  then  allowing  her  to  suckle  her  child  may  result  in  a  disappearance  of  the 
lesions,  and  the  child  may  grow  up  to  be  a  healthy  child,  provided  fiu:ther  treat- 
ment is  prescribed,  it  may  also  have  the  opposite  effect,  and  may  precipitate  the 
end.  The  same  can  be  said  of  giving  an  infant  an  intramuscular  injection  of 
salvarsanised  serum.  As  a  child  born  with  symptoms  runs  a  very  great  risk  of 
dying,  I  certainly  think  the  chance  may  be  taken,  and  one  of  the  latter  two  methods 
adopted,  as  both  of  them  are  safer  than  the  first. 

If  a  child  develops  symptoms  after  birth,  unless  for  exceptional  reasons,  I  do 
not  give  salvarsan,  as  the  judicious  administration  of  mercury  nearly  always 
produces  the  result  desired,  and  I  am  rather  inchned  to  hold  the  view,  that  neither 
the  early  administration  of  mercury  nor  even  of  salvarsan  is  going  to  prevent  the 
patient  from  developing  late  symptoms,  such  as  interstitial  keratitis,  nerve  troubles, 
deafness,  etc.  It  has  been  my  experience,  that  patients  who  develop  late  symptoms, 
such  as  those  just  described,  did  not  have  early  symptoms,  and  vice  versa,  while 
treatment  appeared  to  play  a  subordinate  role. 

In  cases  of  late  congenital  syphilis,  I  have 'never  seen  salvarsan  do  any  good, 
except  in  gunimata,  and  these  I  have  frequently  seen  heal  up  hke  magic,  when 
mercury  and  iodides  would  not  touch  them.  I  am  not  at  all  sure  that  salvarsan 
does  not  aggravate  interstitial  keratitis.  I  have  treated  seventeen  cases,  without 
having  once  noticed  the  shghtest  improvement,  and  in  spite  of  several  injections, 
in  four  of  the  cases  the  other  eye  became  affected  while  the  patient  was  under 
treatment.  I  am  quite  sure  that  it  makes  congenital  sj'philitic  deafness  worse — 
in  fact,  it  is  just  possible  that  it  stimulates  its  appearance. 

In  cases  of  so-called  Syphilis  hereditaria  tarda,  I  have  always  found  mercury 


328  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

and  iodides  to  be  the  best  drugs,  with  the  single  exception  of  the  cases  with 
gummata  of  the  skin,  bones,  etc. 

Intravenous  injection  of  infants  under  six  or  seven  years  of  age  is  no  easy  task, 
hence,  if  salvarsan  is  to  be  prescribed,  it  is  best  administered  intramuscularly.  The 
dose  should  range  from  O'OOl  grm.  to  0"004  grm.  per  lb.  weight.  For  a  child  aged 
seven  not  more  than  0'2  grm.  shoiild  be  given  intravenously.  If  salvarsan  is  to 
be  used  in  congenital  syphihs,  repeated  small  doses,  given  intramuscularly,  is  the 
best  plan  to  adopt,  but  the  treatment  should  invariably  be  supplemented  by  mercury 
and  iodides,  in  the  same  quantities  as  they  would  have  been  prescribed,  had  the 
salvarsan  not  been  given. 

Syphilis  of  the  Nekvous  System. 

Brain. 

Meningeal. 

Meningitis. — Early  meningeal  lesions  should  be  treated  in  the  same  manner 
as  described  under  the  generahsation  stage,  and,  after  six  or  seven  intravenous 
injections  of  neo-salvarsan  have  been  given,  the  patient  should  receive  as  many 
intrathecal  injections  of  salvarsanised  serum  as  are  necessary  to  render  the  fluid 
normal. 

It  must  be  remembered  that  salvarsan  and  neo-salvarsan  have  an  influence 
upon  the  constitution  of  normal  cerebro-spinal  fluid,  hence,  when  it  is  stated  that 
intrathecal  injections  should  be  given  until  the  cerebro-spinal  fluid  becomes  normal, 
certain  reservations  must  be  made. 

The  cerebro-spinal  fluid  to  be  tested,  will  naturally  be  that  taken  when  the 
next  injection  of  the  serum  is  to  be  administered,  hence  an  intravenous  injection 
of  the  arsenic  salt  will  always  have  been  given  24  hours  previously,  and  the  last 
intraspinal  injection  from  seven  to  ten  days  or  more  ago. 

It  will  follow,  therefore,  that,  in  all  cases  in  which  injections  are  being  given 
until  the  cerebro-spinal  fluid  becomes  normal,  treatment  will  be  still  exerting  its 
influence  upon  the  constituents  of  that  fluid. 

I  am  unable  to  tell  yet  for  how  long  such  an  influence  is  exerted,  but  I  do  know, 
as  I  have  found  out  some  years  ago  when  gauging  the  influence  of  treatment  upon 
the  Wassermann  reaction  of  the  blood,  that  even  if  onh'  one  or  two  injections  were 
given,  and  one  or  two  months  were  allowed  to  elapse  before  the  blood  was  tested, 
many  cases  gave  a  negative  reaction,  but  all  recurred  later.  Therefore,  the  negative 
reaction  did  not  signifv  that  sufficient  treatment  had  been  given. 

The  same  happens  with  the  cerebro-spinal  fluid,  and  most  of  the  cases  recur, 
if  only  one  or  two  intraspinal  injections  are  given.     This  being  the  case,  I  made 


THE   TREATMENT   OF   SYPHILIS.  329 

the  rule  to  give  as  many  injections  of  salvarsan  or  neo-salvarsan  as  I  found  were 
necessary  to  produce  a  negative  Wassermann  reaction  in  the  blood  withdrawn 
48  hours  after  the  last  injection.  By  this  means,  I  found  how  many  intravenous 
injections  in  the  early  stages  of  the  disease  were  required.  As  approximately 
the  same  number  was  required  in  most  cases  in  the  same  stage,  I  fixed  upon  the 
maximum,  and  have,  since  early  in  1912,  given  the  number  above  mentioned  to 
every  case  according  to  the  stage  of  the  disease,  with  the  result  that,  provided  the 
mercurial  treatment  has  been  persisted  in,  I  have  had  so  far  very  few  recurrences. 

In  some  of  the  cases,  the  Wassermann  reaction  has  become  positive  again,  but 
I  doubt  whether  that  means  anything,  as  in  most  instances  it  has  been  paradoxical, 
i.e.,  negative  at  one  examination,  positive  at  the  next,  or  vice  versa.  Owing  to  the 
vagaries  of  the  Wassermann  reaction,  I  have  done  for  some  time,  and  do  still,  rely 
upon  my  clinical  experience  ;  that  is  to  say,  I  give  the  treatment  already  specified 
to  every  case  alike,  and  never  regnlate  it  by  the  reaction.  Up  to  the  present,  I  have 
not  had  cause  to  regret  it,  and  I  do  not  think  I  am  Hkely  to  have  cause  for  regret. 
Doubtless  many  cases  receive  too  much  treatment,  but  that  cannot  be  helped,  so 
long  as  we  have  no  accurate  means  of  gauging,  in  each  individual  case,  the  exact 
amount  required. 

At  the  present  moment,  I  am  much  in  the  same  position  as  regards  the  influence 
of  treatment  upon  the  cerebro-spinal  fluid,  as  I  was  in  1911-1912,  when  I  was 
gauging  it  in  the  blood.  I  know  that  two  intraspinal  injections  are  far  from  being 
sufiicient  to  prevent  recurrences  of  meningeal  lesions,  but  I  cannot  gauge  for  certain 
how  many  are  required,  because  I  have  not  had  time  enough  to  watch  my  cases, 
and  I  have  not,  to  my  satisfaction,  worked  out  the  influence  treatment  has  upon 
the  tests  we  employ  in  examining  the  cerebro-spinal  fluid.  In  the  case  of  the  blood, 
we  had  only  the  Wassermann  reaction  to  consider,  but  in  the  case  of  the  cerebro- 
spinal fluid,  we  have  the  amount  of  albumin  and  globulin,  the  number  of  the  cells, 
and  the  Wassermann  reaction  to  take  into  account. 

My  rule,  which  must  needs  be  still  sub  judice  and  hable  to  change,  is  to  give 
about  sis  intraspinal  injections  of  salvarsanised  serum  in  early  meningeal  cases, 
as  I  have  so  far  found  that  this  number  is  usually  required  to  render  the  fluid 
"  normal,"  when  tested  on  the  day  on  which  the  last  injection  is  given. 

A  normal  cerebro-spinal  fluid  after  treatment,  I  regard  as  one  in  which  the  cell 
count  is  not  more  than  12  per  c.mm.  ;  in  which  there  is  only  a  trace  of  giobuhn, 
but  may  be  an  excess  of  albumin  ;  and  one  in  which  the  Wassermami  reaction  is 
negative  in  1,000  per  cent.  Such  a  result,  in  a  patient  who  has  had  no  treatment, 
is  certainly  suggestive  of  the  presence  of  a  morbid  process.  If  the  patient  has 
been  treated  with  salvarsan,  it  is  not  at  all  an  unusual  result  to  find. 


330  THE    BIOLOGY,    CLINICAL  ASPECT   AND   TREATMENT   OF    SYPHILIS. 

Gumma. 

In  any  late  intracranial  lesion,  one  must  always  be  on  guard  against  reactionary 
inflammation,  when  salvarsan  is  prescribed.  In  the  case  of  a  gumma,  and  it  must  be 
remembered  that  cerebral  gummata  are  usually  multiple,  the  reactionary  inflam- 
mation following  intravenous  injections  of  salvarsan  may  be  very  severe,  hence, 
it  is  a  good  plan  to  prescribe  a  course  of  40-60  inunctions  of  mercury  first,  then 
increasing  doses  of  iodides  for  one  month,  and  then,  finally,  intravenous  injections 
of  salvarsan  ma}-  be  given. 

Or  intraspinal  injections  of  salvarsanised  serum  may  be  given  from  the  start, 
as  I  have  never  yet  seen  these  injections  produce  sufiicient  reactionary  inflammation 
to  render  the  patient  comatose. 

Assuming  that  "  606  "  has  been  given  first,  if  reactionary  inflammation  is  going 
to  be  severe  enough  to  make  the  patient  either  temporarily  mad  or  unconscious, 
the  symptoms  will  set  in  suddenly  on  the  third  day,  either  after  the  second  or  the 
third  injection.  Reactionary  inflammation  is  less  severe  after  neo-salvarsan  than 
after  salvarsan,  and  it  may  in  most  cases  be  avoided,  if  not  more  than  two  or  three 
days  are  allowed  to  intervene  between  the  first  three  injections  of  0"45  grm.  The 
objection  to  salvarsan  is  that  such  big  doses  at  such  short  intervals  cannot  be 
given. 

If  the  patient  has  reactionary  inflammation,  subcutaneous  injections  of 
adrenalin  should  be  prescribed,  1  c.c.  of  1  :  1000  solution,  every  four  hours.  Four 
or  five  injections  may  be  given.  A  lumbar  puncture  may  be  done,  but  the  reUef 
which  follows  is  often  only  temporary  and  slight.  The  best  plan  is  to  give  another 
intravenous  injection  of  neo-salvarsan,  and  an  intraspinal  injection  of  the  serum 
next  day.  The  future  course  of  treatment  should  be  undertaken,  as  if  no  reactionary 
inflammation  had  occurred. 

If  the  patient  has  a  Gumma  cerebri,  the  chances  are  that,  however  much 
treatment  be  given,  an  actual  cure  of  the  disease  will  not  be  obtained.  Therefore, 
it  appears  to  me  to  be  better  to  treat  these  cases  symptomatically. 

Let  us  look  back  for  a  moment,  and  see  what  happened  to  the  cases  of  Gumma 
cerebri,  before  the  salvarsan  era.  Mercurial  inunctions,  with  large  doses  of  iodide, 
often  succeeded  in  ridding  the  patient  of  his  symptoms.  Some  recurred  very 
quickly,  others  •went  years  without  a  recurrence.  When  salvarsan  first  came  in, 
one  or  two  injections  were  given,  with  the  result  that  the  symptoms  vanished 
quickly,  but  soon  returned.  When  mercury  was  prescribed  as  well,  and  the  number 
of  injections  was  increased,  so  far  the  cases  have  not  recurred. 

In  any  case,  the  treatment  we  now  adopt  has  not  been  sufiiciently  long  in 
use,  to  allow  us  to  say  that  such  and  such  a  course  should  be  adopted. 


THE   TREATMENT   OF   SYPHILIS.  331 

Therefore,  I  can  only  state  what  appears  to  me,  at  present,  to  be  the  best 
treatment  for  a  case  of  Gumma  cerebri. 

I  give  nine  intravenous  injections  of  neo-salvarsan,  and  use  some  of  these  for 
preparing  the  salvarsanised  serum,  which  I  inject  intraspinally  the  day  following 
the  intravenous  injection.  Between  each  pair  of  the  nine  injections,  four  to  seven 
days  are  allowed  to  elapse  : — 

1.  Intravenous  injection  ;   intraspinal  next  day. 

2.  Intravenous  injection  only. 

3.  Intravenous  injection  ;   intraspinal  next  day. 

4.  Intravenous  injection  only. 

5.  Intravenous  injection  only. 

6.  Intravenous  injection  only. 

7.  Intravenous  injection  ;   intraspinal  next  day. 

8.  Intravenous  injection  only. 

9.  Intravenous  injection  ;   intraspinal  next  day. 

After  that  course  is  finished,  I  prescribe  mercury  and  iodides  for  two  years, 
i.e.,  six  courses,  each  com'se  consisting  of  eight  weekly  intramuscular  injections  of 
grey  oil,  three  weeks  iodides,  and  five  weeks  rest. 

Meningo-encephalitis. 

Many  of  the  statements  made  under  the  preceding  heading,  apply  equally 
well  here,  and  the  treatment  is  identical.  A  cure  can  scarcely  be  exjjected,  but 
a  recurrence  may  be  delayed  for  several  years,  and,  if  the  treatment  is  thorough, 
as  in  every  case  I  think  it  ought  to  be,  the  chances  are  that,  if  a  recurrence  occurs, 
it  will  not  be  degenerative,  as  it  may  be  if  the  previous  treatment  has  been  poor. 
There  is  no  doubt  that  spontaneous  cure  results  in  many  of  these  cases,  and  the 
influence  of  present-day  treatment  upon  such  a  termination  is  a  point  which  requires 
most  careful  consideration,  as  it  is  Ukely  to  be  a  burning  question  in  some  years 
to  come. 

Cases  of  meningo-encephaUtis,  occurring  within  two  years  of  the  infection, 
usually  because  sufficient  treatment  has  been  prescribed  to  steriHse  the  systemic 
portion  of  the  body  only,  require  very  drastic  treatment.  In  these  cases,  I  give 
nine  to  fifteen  intravenous  injections  of  neo-salvarsan,  and  an  intraspinal  injection 
of  salvarsanised  serum  the  day  following  every  alternate  intravenous  injection, 
so  as  to  render  the  cerebro-spinal  fluid  normal.  This  treatment  is  supplemented 
by  mercury  and  iodides  for  two  years.  Cases  of  meningo-encephalitis,  occurring 
after  the  period  just  mentioned,  should  be  treated  symptomatically,  but  nevertheless 
thoroughly,  because  the  more  thorough  the  treatment,  the  less  the  probabihty  of 


332  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

the  recurrence  being  of  a  degenerative  nature,  and  vice  versa.  Such  a  statement 
must,  in  the  present  imperfect  state  of  our  knowledge,  be  based  mainly  on  theory. 

Late  cases  of  meningo-encephahtis  should  be  treated  in  the  same  way  as  described 
under  the  heading  gumma.  The  chances  of  severe  reactionary  inflammation  are 
greater  in  cases  of  meningo-encephahtis  than  they  are  in  Gumma  cerebri,  but  if 
three  injections  of  neo-salvarsan  be  given,  two  of  which  form  the  first  stage  of  the 
intraspinal  injection,  severe  reactionary  inflammation  can  be  almost  invariably 
avoided. 

To  show  how  quickly  an  intraspinal  injection  of  salvarsanised  serum  will  stop 
reactionary  inflammation,  the  following  case  of  meningo-encephalitis  will  form  a 
good  example  : — 

Case  49. — Man,  aged  29.  Infection  in  1911.  Early  in  1914,  patient  com- 
plained of  bad  headaches,  which  steadily  become  worse.  On  two  occasions  he  had 
a  fit.  I  saw  him  in  July,  1914,  and  the  following  is  an  outhne  of  what  I  found. 
Patient  thin,  had  rapidly  lost  weight,  could  not  sleep  very  well,  he  was  apathetic, 
and  slow  in  answering  questions.  All  the  reflexes  were  exaggerated.  The  pupils 
were  unequal,  and  so  were  the  pupillary  reflexes.  Cerebro-spinal  fluid  showed 
marked  pathological  changes. 

Patient  was  given  at  the  hospital  three  intravenous  injections  of  neo-salvarsan. 
On  the  third  day  after  the  last  injection,  the  patient  became  comatose,  and  all  the 
chnical  signs  were  intensified.  I  drew  oft'  50  c.c.  of  blood,  and  injected  intra- 
spinally,  the  next  day,  25  c.c.  of  serum  mixed  with  the  same  quantity  of  sahne, 
after  having  drawn  off  a  nearly  equivalent  amount  of  cerebro-spinal  fluid.  The 
next  day,  the  patient  was  sitting  up  and  tallcing  as  if  nothing  had  happened. 
Further  treatment  was  continued,  without  any  untoward  eft'ect. 

The  main  change  in  the  cerebro-spinal  fluid  in  these  cases  of  severe  reactionary 
inflammation  is,  besides  the  great  rise  of  pressure,  the  tremendous  increase  of  the 
albumin  content. 

Degenerative  Encephalitis. 

If  the  case  has  obviously  been  of  meningeal  origin,  treatment  may  be  prescribed 
more  with  the  idea  of  lengthening  the  period  of  quiescence,  since  the  cases  all  recur 
in  time,  however  drastic  the  treatment  may  be.  Nibbhng  treatment  does  the 
patient  more  harm  than  good,  and  treatment  should  never  be  prescribed  during 
a  quiescent  period,  for  fear  of  precipitating  an  attack. 

If  it  is  the  patient's  first  attack,  I  give  six  to  eight  intraspinal  injections  of 
salvarsanised  serum,  at  seven  to  fourteen  days'  interval  between  each  pair,  and 
mercurv  and  iodides  for  a  vear. 


THE   TREATMENT   OF    SYPHILIS.  333 

Giving  only  one  or  two  intravenous  injections  of  neo-salvarsan,  or  one  or  two 
intraspinal  injections  of  salvarsanised  serum,  has,  in  my  experience,  made  the 
patient  worse.  If  it  is  the  patient's  second  attack,  I  do  not  think  any  anti-syphihtic 
treatment  ought  to  be  given. 

Cases  in  which  no  anti-syphihtic  treatment  is  recommended,  should  all  receive 
hexamethylene  tetramine  internally,  and  if  the  relatives  are  anxious  that  something 
should  be  done,  injections  of  nucleinate  of  soda  can  be  given. 

Pilcz^  and  Wagner  v.  Jauregg^  advocated,  some  years  ago,  tubercuHn  injections 
and  large  doses  of  staphylococcic  and  streptococcic  vaccines.  The  idea  was  purely 
empirical,  and  was  due  to  the  observation  that  had  frequently  been  made,  that 
intercurrent  febrile  processes  sometimes  exerted  a  beneficial  effect  upon  the  course 
of  degenerative  encephahtis. 

Both  act  in  virtue  of  their  capacity  of  producing  a  rise  in  temperature,  and,  since 
nucleinate  of  soda  is  far  more  powerful  in  this  respect,  it  has  entirely  taken  the 
place  of  tubercuhn  and  the  vaccine  of  the  pyogenic  cocci. 


Ameningeal. 

In  pure  arterial  lesions  without  involvement  of  nerve  substance,  such  as  in  the 
early  form  of  hemiplegia,  the  case  should  be  treated  as  described  under  the  generaUsa- 
tion  stage,  and  there  is  no  necessity  to  examine  the  cerebro-spinal  fluid. 

It  is  imperative  to  treat  these  cases  at  once,  so  as  to  avoid  subsequent  con- 
tractures, etc.,  resulting  from  the  paralysis. 

In  later  cases,  such  as  encephalitis  or  gumma,  the  treatment  should  be  the 
same  as  that  already  mentioned  for  similar  lesions  of  meningeal  origin. 

In  cases  of  ameningeal  degenerative  encephahtis,  anti-syj^hihtic  treatment  is 
contra-indicated,  even  if  it  is  the  patient's  first  attack.  Hexamethylene  tetramine 
should  be  given  internally,  and  intramuscular  injections  of  nucleinate  of  soda 
may  be  given  if  desired. 

The  most  difficult  cases  to  treat  are  the  late  cases  of  hemiplegia.  If  the  patient 
comes  up  with  premonitory  signs,  such  as  an  ocular  palsy,  it  is  certainly  worth 
while  to  give  him  seven  or  eight  intravenous  injections  of  neo-salvarsan — never 
salvarsan,  as  "  606  "  is  apt  to  cause  marked  variations  in  the  blood  pressure,  such 
as  I  have  not  noticed  with  "  914."  Mercury  should  be  given  for  a  year,  either  in 
the  form  of  pills  or  suppositories,  and  the  patient  should  be  more  or  less  under 
iodides  for  the  remainder  of  his  hfe. 

The  iodides  .can  be  prescribed  in  the  form  of  tiodiue  pills,  of  which  the  patient 
should  take  one  or  two  a  day. 


334:  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT    OF   SYPHILIS. 

If  the  patient  has  already  got  hemiplegia,  nothing  in  the  way  of  anti-syphilitic 
treatment  will  do  much  good,  but  iodides  ought  certainly  to  be  prescribed. 

Haemorrhagic  encepJutlilis. — When  this  condition  follows  the  second  or  the 
third  injection  of  salvarsan  in  the  generalisation  stage,  the  patient,  the  moment  he 
becomes  unconscious  or  in  any  way  strange,  should  receive  intramuscular  injections  of 
adrenahn,  and  an  intraspinal  injection  of  his  own  serum,  or  of  a  serum  obtained  from 
another  human  being.  In  the  lymphocytic  type  which  occurs  later  in  syphihs,  and  is 
usually  independent  of  treatment,  or,  as  I  showed  in  Chapter  XXIV,  which  may  come 
on  some  weeks  or  months  after  inadequate  treatment,  the  patient  must  be  put  under 
treatment  before  he  loses  consciousness,  because,  if  there  is  any  delay,  death  will  ensue. 

Adrenalin  should  be  given  as  before,  and  intrathecal  injections  of  either 
ordinary  serum  or  of  salvarsanised  serum  should  be  prescribed  as  quickly  as  possible. 
There  is  no  risk  of  producing  reactionary  inflammation  in  such  a  case  with  salvarsan 
or  neo-salvarsan,  provided  an  intrathecal  injection  of  serum  is  given  the  following 
day.  Once  the  patient  has  recovered,  even  in  cases  of  haemorrhagic  encephalitis, 
it  is  perfectly  safe  to  continue  the  treatment  as  if  nothing  had  happened. 

Coed. 
Meningeal. 

In  all  cases  of  meningitis  of  the  cord,  it  must  be  assumed  that  there  is  intra- 
cranial meningitis  also.  This  being  the  case,  and  since  reactionary  inflammation 
can  never  do  any  damage  or  produce  serious  symptoms,  owing  to  the  comparatively 
large  space  in  which  the  cord  lies,  there  is  need  only  to  think  of  what  may  happen 
in  the  cranium,  hence  the  treatment  just  described  will  be  equally  applicable  here. 

The  same  may  be  said  about  gummata  and  meningo-myelitis. 

In  degenerative  myelitis  of  meningeal  origin,  treatment  should  invariably  be 
prescribed,  should  the  symptoms  be  such  as  to  worry  the  patient,  or  should  the 
cerebro-spinal  fluid  show  pathological  changes,  and  the  case  appears  obviously 
to  be  progressing.  In  such  cases,  eight  to  eleven  intraspinal  injections  of  salvar- 
sanised serum  should  be  given,  and  mercury  continued  for  one  year,  or  perhaps 
two,  if  it  appears  to  be  benefiting  the  patient.  The  mercury  should,  preferably, 
be  given  in  the  form  of  intramuscular  injections. 

If  the  cerebro-spinal  fluid  is  normal,  and  the  lesion  appears  to  have  spontaneously 
healed,  which  is,  by  the  way,  not  at  all  an  uncommon  sequence,  treatment  should 
only  be  prescribed  should  troublesome  symptoms  still  persist,  and  then  the  treatment 
should  only  be  symptomatic.  The  following  case  will  give  the  reader  exactly  what 
is  meant  by  the  above  : — 

Case  50. — A  man,  aged  43,  contracted  syphilis  when  19  years  of  age.     Teu 


THE   TREATMENT   OF    SYPHILIS.  335 

years  after  infection,  he  developed  typical  signs  of  degenerative  myelitis.  I  saw 
him  first  in  December,  1909,  when  he  had  Argyll-Robertson's  pupils,  very  slight 
rhombergism,  altered  sensations  down  the  ulnar  region  of  both  arms  and  in  both 
feet.  The  knee-jerks  were  absent.  He  complained  of  severe  pains  in  his  feet, 
ankles,  and  legs,  and  also  that  he  could  not  get  an  erection.  I  advised  mercurial 
inunctions,  and  potassium  iodide  and  arsenic  internally.  I  saw  the  patient  about 
two  years  later,  when  he  informed  me  that  the  pains  were  as  bad  as,  if  not  worse 
than,  ever.  I  then  gave  him  foiu-  intravenous  injections  of  salvarsan,  at  about  ten 
days'  interval  between  each  pair,  after  having  first  examined  his  cerebro-spinal  fluid, 
which  turned  out  to  be  normal.  This  treatment  did  not  appear  to  do  him  much 
good.  During  the  year  1912,  I  ordered  him  four  courses,  each  course  consisting 
of  thirty  intramuscular  injections  of  oxycyanide  of  mercury  and  acoine  (Hirsch's 
injection).  These  injections  produced  only  a  little  temporary  relief.  I  examined 
the  cerebro-spinal  fluid  again  in  April,  1913,  with  the  same  result  as  before.  I 
might  say  that  the  Wassermann  reaction  in  the  blood  was  negative  throughout. 
In  October,  1913,  the  pains  were  particularly  severe,  and  the  patient  began  to 
develop  painless  whitlows  on  both  hands.  No  sooner  had  one  healed  than  another 
appeared,  so  I  gave  him  an  intraspinal  injection  of  salvarsanised  serum.  The 
injection  produced  such  an  aggravation  of  the  pains  that  he  had  to  be  kept  under 
morphia  for  two  days,  and,  twenty-four  hours  after  the  injection,  he  developed  the 
biggest  whitlow  that  he  liad  ever  had. 

When  he  recovered  from  the  exacerbation  of  the  symptoms,  he  remained 
practically  free  of  pain  for  three  months,  when  they  recommenced,  but  not  with  the 
same  severity.     One  or  two  small  whitlow's  occurred  in  the  meantime. 

I  repeated  the  intraspinal  injection  in  February,  1914.  The  cerebro-spinal 
fluid  was  normal,  as  it  has  been  since.  The  exacerbation  of  pains  did  not  come 
on  so  quickly,  it  was  not  so  severe,  in  fact  no  morphia  was  required,  but  it  was  longer 
in  going  off,  and  there  was  no  whitlow. 

The  patient  had  comparative  freedom  till  June,  191-4,  when  the  pains  began 
again,  but  nothing  like  so  severely  as  before,  and  he  had  only  one  whitlow. 

I  gave  the  third  intraspinal  injection  in  July,  1914,  and  the  fourth  in  December, 
1914.  Hardly  any  exacerbation  of  the  pains  was  produced  by  either.  The  pains 
have  been  comparatively  mild  and  easily  assuaged  by  aspirin,  and  no  whitlow  has 
developed.  The  patient  has  put  on  weight,  which  is  always  an  extremely  good 
sign  iu  any  syphiHtic  nervous  trouble,  especially  if  it  is  degenerative,  but  the  signs 
have  throughout  remained  unaltered. 

Enesol  is  sometimes  advocated  for  pains  in  cases  of  degenerative  myeUtis,  but 
I  must  admit,  that  in  my  hands,  it  has  never  produced  any  relief. 

Y 


336  THE    BIOLOGY,    CLINICAL   ASPECT   AXD   TREATMENT   OF   SYPHILIS. 

Anieningeal. 

Ill  transverse  myelitis,  treatment  mnst  be  begnn  at  once,  and  it  shonld  be  the 
same  as  that  described  under  the  generaUsation  stage.  As  it  is  an  arterial  lesion, 
therefore  there  is  no  need  to  give  any  intraspinal  injections.  To  show  the  extra- 
ordinary benefits  that  may  follow  appropriate  treatment,  I  will  cite  a  case  which 
I  treated  in  1912,  ■when  neo-salvarsan  first  came  in. 

Case  51. — A  man,  aged  25,  had  contracted  syphilis  eighteen  months  prior  to 
suddenly  becommg  paralysed  in  both  his  legs.  When  I  saw  him,  he  had  complete 
paraplegia,  and  had  lost  the  control  of  both  his  vesical  and  rectal  sphincters. 

I  gave  him  nine  intravenous  injections  of  neo-salvarsan,  and  mercury  and 
iodides  for  two  years.  In  August  of  1912,  the  injections  having  been  given  in 
April,  the  patient  was  playing  tennis. 

If  the  vessel  has  been  allowed  to  become  permanently  blocked,  treatment 
will  aid  the  patient,  but  serious  defects  will  naturally  remain  in  spite  of  it,  therefore 
it  cannot  be  stated  too  often,  that  not  an  hour  should  be  lost  in  putting  under 
treatment  every  patient  with  an  arterial  lesion  occurring  in  early  s}'philis. 

In  late  cases  of  myelitis,  in  cases  of  lateral  sclerosis  and  atrophic  muscular 
paralysis,  very  little  can  be  done  by  treatment,  but,  as  treatment  will  do  no  harm, 
it  should  certainly  be  tried. 

If  the  condition  appears  to  benefit  by  one  or  two  intraspinal  injections  of 
salvarsanised  serum,  the  treatment  should  be  continued  until  about  8-11  have  been 
given.  If  no  improvement  appears,  then  nothing  is  to  be  gained  by  persevering 
with  treatment. 

If  the  cerebro-spinal  fluid  is  examined  first,  and  found  to  be  normal,  no  treat- 
ment need  be  prescribed,  and  this  apphes  equally  well  to  cases  of  degenerative 
myelitis  of  ameningeal  origin.  If,  on  the  other  hand,  the  fluid  shows  pathological 
changes,  and  the  patient  is  worried  by  his  symptoms,  treatment  should  be  given, 
as  there  is  no  fear  of  hastening  the  end,  as  is  the  case  in  amenmgeal  degenerative 
encephalitis. 

Cases  of  combined  degenerative  myehtis  and  encephahtis  are  best  treated 
with  nucleinate  of  soda,  and  not  with  anti-syphihtic  remedies. 

In  no  condition  is  individual  treatment  more  necessary  than  in  nervous  s\-philis, 
and  although  I  have  attempted,  as  clearly  as  possible,  to  narrate  the  methods  I 
employ,  it  must  be  understood  that  every  case  has  to  be  judged  upon  its  own  merits. 

»  McDonagh  (1911),  "  Brit.  .Journ.  of  Derm.,"  xxiii,  227. 

"  Pilcz  (1911),  "  Zeitschr.  f.  d.  Ges.  Neiir.  u.  Psych.,"  iv  (orig.),  457. 

»  Wagner  v.  Jauregg  (1912),  "  Wien.  klin.  Woch.,"  xxv,  61. 

'  Homer  Swift  and  Ellis  (1913),  "  .Journ.  of  the  Amer.  Med.  Assoc.,"  Ix.  1.576. 


CHAPTER  XXX. 

DRUGS  USED  IN  THE  TREATMENT  OF  SYPHILIS,  AND  THE  METHODS 

OF  ADMINISTERING  THEM. 

The  di-ugs  we  have  to  consider  are,  salvarsan,  neo-salvarsan,  other  arsenical 
compounds,  antimony,  mercury,  iodine,  and  nucleinate  of  soda. 

Salvarsan  and  Neo-salvarsan. 
A. — Intramuscular  Injection  of  Salvarsan. 

The  yellow  powder  being  acid,  alkali  must  be  added  before  its  solution  can 
be  injected.  Sodium  hydrate  is  the  alkali  most  frequently  employed,  and  excess 
of  it  can  be  neutralised  or  not ;  if  it  be  neutralised,  the  pain  is  not  so  severe,  and 
an  emulsion  is  formed,  which  has  the  distinct  disadvantage  of  not  being  so  quickly 
absorbed,  but  may  become  encapsuled  by  the  tissues,  and  an  arsenic  depot  formed. 
As  the  pain  produced  by  the  injection  is  so  severe,  the  method  is  seldom  employed. 
It  has  another  objection,  in  that  the  bulk  of  fluid  is  large,  so  that  two  injections 
have  to  be  made. 

Dissolve  the  powder  in  alcohol — ethyl  alcohol  for  choice — not  methyl  alcohol, 
as  has  been  advocated,  because,  unless  absolutely  chemically  pure,  it  may  give 
rise  to  unpleasant  symptoms,  probably  dependent  on  the  presence  of  formaldehyde, 
which  is  not  an  uncommon  impiirity.  0"5  c.c.  of  alcohol  is  used  for  every  0"  1  grm. 
of  powder,  and  20  c.c.  of  ordinary  sterile  warm  M-ater  are  added,  and  the  mixture 
stirred  with  a  glass  rod  until  every  trace  of  the  powder  is  dissolved  ;  then  add 
slowly,  mixing  thoroughly  while  adding,  1  c.c.  of  decinormal  sodiiim  hydrate 
solution  to  each  O'l  grm.  of  powder  used.  Inject  equal  quantities  into  each 
buttock,  at  the  junction  of  the  outer  and  middle  third  of  a  line  drawn  from  the 
top  of  the  greater  trochanter  to  the  sacral  spines,  using  a  needle  not  less  than 
2  ins.  long.  The  preparation  which  is  now  sold  as  salvarsan  requires  no  alcohol 
to  dissolve  it,  and  thereby  the  pain  is  considerably  modified.  If  the  solution  is 
intended  to  be  neutralised,  the  best  plan  of  procedure  is  as  follows  : — 

Put  the  powder  into  a  mortar  and  add  1  c.c.  of  a  saturated  solution  of  sodium 
hydrate,  mix,  and  then  dissolve  in  4  c.c.  of  very  hot  water  ;  as  an  indicator,  3  drops 

y2 


338  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

of  the  standard  alcoholic  solution  of  phenolphthalein  are  added,  which  colour  the 
solution  a  bright  red  ;  then  add  glacial  acetic  acid,  drop  by  drop,  till  a  yellow 
emulsion  is  produced  ;  finall)',  put  in  one  or  two  drops  of  sodium  hydrate  until 
the  emulsion  assumes  a  rose-pink  tint.  This  emidsion  is  taken  up  in  the  syringe, 
and  any  residue  left  in  the  mortar  can  be  drawn  up  by  adding  another  1  to  2  c.c. 
of  hot  water.  The  injection  need  not  necessarily  be  made  in  the  glutei,  a  useful 
fact  to  remember  with  male  patients  who  take  to  bed  badly.  Pain  is  often  more 
severe  in  this  situation  when  the  patient  is  recumbent,  than  when  he  is  up  and 
about,  but,  unfortunately,  movement  excites  local  reaction,  mth  the  result  that  the 
injected  mass  tends  to  gravitate  downwards  on  to  the  sciatic  nerve,  producing 
sciatica,  which  necessitates  a  prolonged  stay  in  bed. 

A  favourite  place  for  an  injection  is  into  the  trapezius  muscle,  near  the  vertebral 
column,  and  just  below  the  angle  of  the  scapula,  on  the  left  side  in  right-handed 
individuals  and  vice  versa.  There  is  often,  especially  in  plethoric  subjects  difEculty 
in  breathing,  owing  to  spasm  of  the  intercostal  muscles,  immediately  after  injection 
into  the  shoulder,  but  it  seldom  lasts  longer  than  a  quarter  of  an  hour.  It  is  often 
accompanied  by  coughing,  but  in  only  one  case  did  the  patient  become  cyanosed 
and  pleurisy  develop.     It  is  better  to  inject  emphysematous  patients  in  the  glutei. 

The  following  is  the  best  method  of  preparing  a  neutral  emulsion  . — 

Neutral  Emulsion  {Citron's  Method). — The  contents  of  a  tube  are  emptied  into 
a  glass,  and  then  1  c.c.  of  absolute  alcohol  and  5  c.c.  of  hot  water  are  added  and 
the  mixture  stirred  until  all  the  powder  is  dissolved.  Next,  40  drops  of  a  10  per 
cent,  solution  of  potassium  bicarbonate  in  normal  saline  are  added.  The  mixture 
is  now  stirred  carefull}'  with  a  glass  rod  until  an  emulsion  is  produced,  when  it  is 
drawn  into  the  syringe,  which  must  be  inverted  to  get  rid  of  the  air.  As  this 
emulsion  is  sometimes  thick,  a  pleural-efPusion  needle  should  be  employed,  for 
preference  a  platinum  one  with  an  iridium  point.  Although  the  pain  is  very  much 
lessened,  there  may  be  a  very  painful  toxic  oedema,  unless  the  patient  remains 
quiet  for  a  few  days. 

The  injection  should  always  be  employed  fresh,  and  preferably  made  at  the 
bedside.  Any  tube  opened  and  unused  that  day,  must  not  be  kept  for  another,  as 
this  procedure  has  in  some  cases  resulted  in  toxic  symptoms  supervening,  such  as 
anuria,  inflammation  of  the  bladder,  and  atony  of  the  large  intestine. 

The  best  intramuscular  injection  is  a  new  preparation  called  "  loha."  It 
contains  40  per  cent,  salvarsan  in  iodipin,  and  is  already  prepared  for  use.  It 
keeps  well,  and  the  injection  is  practically  painless. 

Intramuscular  injections  must  always  be  preferred  to  subcutaneous  ones,  as 
the  pain,  swelling,  and  liability  to  necrosis  are  less.     If  complete  aseptic  precautions 


METHODS   OF   USING   ANTI-SYPHILITIC  DRUGS.  339 

are  taken,  an  abscess  will  not  result  from  an  intramuscular  injection.  Directly  after 
the  injection,  the  pain  is  very  acute,  owing  to  the  sudden  distension  of  the  tissues. 
This  persists  for  about  ten  or  fifteen  minutes,  and  is  followed  by  a  dull  aching  pain, 
which  varies  in  its  duration  from  one  to  three  weeks.  On  the  third  day,  a  large  tender 
swelling  may  form,  due  to  toxic  oedema,  which  is  best  relieved  by  alternate  applica- 
tions of  an  icebag  and  hot  fomentations.  AVlien  the  swelling  gets  smaller,  nothing 
gives  the  patient  more  relief  than  the  application  of  a  belladonna  plaster,  which 
also  aids  absorption.  Morphia  may  or  may  not  be  necessarj-.  Pain,  which  is  less 
in  women  than  in  men,  varies  enormously  with  the  individual,  but  is  generally 
sufficient  to  prevent  sleep  for  a  few  nights.  Temperatm'e  may  rise  the  first  night, 
but  more  frequently  on  the  second  and  third  ;  on  the  fourth  day  it  usuallj*  falls,  but 
it  may  persist  for  another  day  or  two.  Occasionally  the  temperature  rises  as  high 
as  103°,  and  although  the  rise  seems  to  be  in  direct  ratio  to  the  severity  of  the 
infection,  it  is  not  invariably  so.  Sometimes,  on  the  second  or  third  day,  the  patient 
complains  of  a  sore  throat.  Constipation  after  injection  is  so  usual,  that  a  laxative 
the  evening  after  the  injection  is  advisable. 

Clinical  Course  after  an  Intrarmiscular  Injection. — However  the  solution  be 
prepared,  and  however  carefidly  it  may  be  given,  one  can  never  say  beforehand 
how  much  pain  the  patient  is  going  to  suffer.  Some  patients  have  little  or  none, 
whilst  others  have  excruciating  pain  which  may  last  as  long  as  a  week.  Needless 
to  say,  the  very  greatest  precaution  should  be  taken  in  sterilising  everything  before 
use,  since,  if  an  abscess  forms,  the  pain,  will  necessarily  be  severe.  Even  when  the 
strictest  antiseptic  precautions  are  taken,  swelling,  softening,  and  necrosis  of  the 
part  injected  may  take  place.  The  swelling  is  a  toxic  oedema  ;  it  comes  on  about 
the  third  day,  diminishes  rapidly  in  size  at  the  end  of  a  week  or  ten  days,  after 
which  its  diminution  is  so  gradual  that  a  small  amount  of  infiltration  may  be 
perceptible  months,  and  even  years  after.  As  a  rule,  the  swelling  is  not  painful ; 
it  gives  the  sensation  of  fluctuation,  but  under  no  circumstances  should  it  be  opened, 
unless  an  obvious  abscess  forms,  when  it  becomes  acutely  painful.  The  skin  over  it 
is  at  fii'st  slightly  red  ;  but  if  it  becomes  red  for  the  first  time  at  the  end  of  a  week,  an 
abscess  must  be  feared.  The  redness  which  appears  with  the  swelling,  is  analogous 
to  that  met  with  in  urticaria,  and  c^uickl}'  disappears  under  an  application  of  the 
following  lotion  : — 

R  Plumbi  subacetat.         . .         . .  . .  gr.  x 

Liq.  ammon.  fort.  . .  . .  . .  n^v 

Spir.  vini  rect.    . .         . .         . .  . .  5] 

Solut.  alumin.  acetat.,  3  per  cent.  . .  ad  j] 


340  THE   BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

When  the  swelling  appears,  alternate  hot  and  cold  applications  give  the  patient  the 
most  relief ;  and,  when  up  and  about,  a  belladonna  plaster  helps  to  diminish  the 
pain  and  increases  absorption.  Even  after  two  or  three  weeks,  the  swelling  may 
be  so  perceptible  as  to  be  visible  through  the  patient's  clothes. 

Occasionally  the  swelling  resolves  into  fluid,  and  in  such  circumstances  it  is 
either  best  left  alone — since  it  causes  the  patient  no  inconvenience — or  the  sterile 
pus  may  be  aspirated.  Under  no  circumstances  should  an  incision  be  made,  since 
a  sterile  abscess  is  thus  almost  certainly  converted  into  an  infected  one. 

Necrosis,  to  a  slight  degree,  occurs  after  every  intramuscular  injection,  but  a 
necrosis  of  the  overlying  skin  occurs  only  when  an  injection  is  given  subcutaneously, 
or  when  some  of  the  mass  is  allowed  to  get  into  the  subcutaneous  tissue,  as  the 
needle  is  withdrawn  from  the  muscle. 

One  of  the  most  important  points,  in  giving  an  intramuscular  injection,  is  to 
avoid  the  entrance  of  any  of  the  emulsion  into  a  vein.  The  needle  should  be  first 
inserted,  and  from  30  seconds  to  a  minute  should  elapse,  before  the  syringe  is 
fastened  on  to  it.  One  case,  where  this  precaution  was  neglected,  resulted  in  the 
patient  getting  hemiplegia,  and  this  complication  was  described  as  being  due  to 
the  toxic  action  of  "  606." 

Necrosis. — In  the  muscle,  or  in  the  subcutaneous  tissue,  lies  a  hardish  mass  of 
brownish-yellow  colour,  in  the  centre  of  which  is  a  dark  brown  horny  mass,  which 
spreads  out  here  and  there  into  the  tissues.  The  central  portion  is  due  to  a  chemical 
action  which  destroys  the  structure  of  the  tissue.  Around,  there  is  usually  a  capsule 
and  marked  signs  of  chronic  inflammation.  Microscopically,  the  necrosis  is  found 
to  affect  muscle,  fat,  and  connective  tissue,  the  nuclei  of  which  do  not  stain.  The 
vessels  in  the  immediate  neighbourhood  of  the  necrosis  are  thrombosed.  Cases  of 
pulmonary  embolism  and  hemiplegia,  coming  on  a  week  or  two  after  an  intramuscular 
injection,  are  probably  due  to  a  thrombus  becoming  detached  and  passing  free  into 
the  blood  stream,  rather  than  to  the  toxic  action  of  salvarsan.  In  the  outer  zone, 
the  thrombosis  is  often  only  partial,  or  the  vessels  are  found  to  contain  collections 
of  leucocytes.  The  nerves  in  the  necrosis  also  degenerate.  Arsenic  is  almost 
invariably  to  be  found,  often  as  late  as  three  or  foiir  months  after  the  injection 
was  given. 

Necrosis  occurs  only  when  a  large  quantity  of  the  preparation  is  injected  in  one 
spot,  and  not  when  several  small  points  in  both  buttocks  are  chosen ;  it  is 
more  common  when  the  injection  is  given  in  the  thoracic  region  than  in  the  glutei. 

There  is  no  doubt  that  one  or  two  of  the  cases  described,  in  which  peroneal 
atrophy  has  set  in  after  an  injection,  were  due  to  an  inflammation,  or  even  to  a 
degeneration  of  the  sciatic  nerve,  caused  by  the  necrosis,  and  not  to  a  nem'otropic 


METHODS    OF   USING    ANTI-SYPHILITIC    DRUGS.  341 

action  of  the  drug.  Moreover,  some  of  the  bladder  and  colon  troubles,  which  have 
occurred  more  frequently  after  an  intragluteal  injection,  may  be  reflex  from  an 
implication  of  the  pudendal  plexus,  which  lies  in  close  relation  to  the  sciatic  nerve. 

B. — Intramuscular  Injection  of  Neo-salvarsan. 

All  that  is  necessary  is  to  dissolve  the  salt  in  saline.  As  neo-salvarsan  is  readily 
soluble,  it  does  not  matter  how  much  saline  is  used ;  I  grm.  of  neo-salvarsan  can  be 
dissolved  in  10  c.c.  of  saline.  Although  the  pain  is  not  so  acute  as  when  salvarsan 
is  used,  it  is  not  often  that  the  patient  will  submit  to  a  second  injection.  It  has 
been  frequently  ad\'ised  to  give  several  injections  of  very  small  doses,  but  the 
therapeutic  action  of  such  a  procedure  is  not  very  satisfactory,  and  this  mancEuvre 
has  the  other  disadvantage,  in  the  fact  that  the  cells  soon  become  accustomed  to 
the  drug — that  is  to  say,  immune  to  it. 

C. — Intravenous  Injection  of  Salvarsan. 

The  contents  of  one  tube  of  salvarsan  should  be  slowly  dissolved  in  3  or  4  ozs. 
of  warm  physiological  0'9  per  cent,  saline  which  has  been  prepared  with  freshly 
distilled  water,  in  a  10-oz.  graduated  glass  measure. 

When  the  powder  has  completely  dissolved  after  sufficient  stirring  with  a  glass 
rod,  10  c.c.  of  double  decinormal*  sodium  hydrate  solution  should  be  added,  with 
the  result  that  a  precipitate  forms.  This  precipitate  is  dissolved  by  a  further 
addition  of  sodium  hydrate,  usually  about  10  c.c. — this  may  be  either  more  or  less, 
according  to  the  actual  acidity  of  the  powder.  The  10  c.c.  should  be  added  slowly, 
and  the  mixture  stirred  thoroughly.  By  using  a  weak  solution  of  sodium  hydrate, 
we  avoid  the  risk  of  making  the  solution  too  alkaline,  and  the  exact  quantity 
required  is  more  easily  estimated.  When  the  solution  is  quite  cleared  by  adding 
the  sodium  hydrate,  the  measure  should  be  filled  with  saline  up  to  10  ozs.,  and 
once  or  twice  filtered  through  muslin  or  several  layers  of  plain  gauze,  so  as 
absolutely  to  exclude  even  the  smallest  solid  particle  from  getting  into  the  vein, 
where  it  might  cause  either  a  pulmonary  embolism  or  hemiplegia ;  10  ozs.  must 
be  considered  the  maximum  dose. 

Two  points  must  be  observed  concerning  the  saline.  In  the  first  place,  the 
sodium  chloride  must  be  chemically  pure  ;  secondly,  the  solution  must  not  be 
less  than  0'8  per  cent,  or  more  than  1  per  cent.  A  hypotonic  solution  is  more 
dangerous  than  a  hypertonic  one,  because  the  former  causes  haemolysis — setting 
free  the  haemoglobin  from  the  red  blood  corpuscles.     Should  this  happen,  the 

*  Double  decinormal  NaOH  or  %  NaOH  =  0-8  per  cent.,  or  8  grm.  to  the  litre  of  distilled 
water,  normal  sodium  hydrate  being  a  4  per  cent,  solution. 


342  THE   BIOLOGY,    CLINICAL  ASPECT   AND    TREATMENT   OF   SYPHILIS. 

patient  may  collapse  after  the  injection,  and  there  may  be  haemoglobinuria. 
Needless  to  say,  every  vessel  used  should  be  sterile,  and  the  sodium  hydrate  solution 
should  be  boiled  before  use. 

Another  vessel  filled  with  saline  is  placed  by  the  side  of  the  one  containing 
the  "  606."  The  patient  comes  to  the  side  of  the  bed  and  hangs  his  arm  over, 
then  a  tourniquet*  is  placed  on  the  arm,  and  the  limb  made  to  rest  on  a  table  in 
as  comfortable  a  position  as  possible.  The  bend  of  the  elbow  is  then  sterilised, 
by  first  rubbing  with  acetone,  and  then  with  ordinary  tinctm'e  of  iodine. 

When  a  vein  cannot  be  seen,  it  can  often  be  felt,  and  should  be  marked  out 
with  a  blue  pencil  to  indicate  its  course.  If  this  cannot  be  done,  a  vein  shovdd 
be  exposed  by  an  incision,  either  under  a  local  or  a  general  anaesthetic.  There  is 
no  danger  in  a  general  anaesthetic,  for  the  subsequent  reaction  is  not  in  any  way 
influenced.  Bitting  the  bend  of  the  elbow,  or  warming  the  arm  with  hot  towels, 
will  often  make  a  vein  prominent.  An  intravenous  injection  may  be  the  simplest, 
or  one  of  the  most  difficult  operations  possible.  A  common  troiible  is  due  to  the 
vein  slipping  about  when  the  needle  tries  to  pierce  it;  extending  the  arm  as  much 
as  possible,  or  pulling  the  skin  taut  to  fix  the  vein,  may  prevent  this. 

The  solution  can  either  be  injected  or  transfused,  injection  being  far  preferable, 
as  : — 

(1)  The  needle  is  not  so  easily  dislodged.  If  this  should  occur  while  the 
solution  is  flowing  in,  by  transfusion  some  must  escape  into  the  tissues  before  the 
flow  can  be  stopped ;  with  the  syrmge,  merely  a  few  drops  need  escape,  as  the  tap 
can  be  turned  ofi  at  once. 

(2)  The  operator  has  more  control  over  the  proceedings. 

(3)  There  is  less  danger  of  air  or  a  solid  particle  gaining  access  to  the  vein. 
Air  is  easily  seen  in  the  syringe  and  remains  at  the  top,  never  coming  over  the 
centre  of  the  outlet  unless  the  piston  is  pushed  right  home.  A  solid  particle  is  also 
seen  ;  it  falls  to  the  bottom  of  the  syringe  and  is  not  disturbed,  provided  that  the 
solution  is  injected  slowly  and  steadily  and  the  piston  not  rammed  home. 

(4)  The  operation  is  pleasanter  from  the  patient's  point  of  view,  because  it  is 
so  much  quicker. 

(5)  The  operation  can  be  performed  without  an  assistant,  and  there  is  prac- 
tically no  apparatus  to  carry  about. 

A  good  syringe  is  one  invented  by  Schreiber.  The  cannula  is  bayonet-shaped, 
bent,  and  fixed  to  a  three-way  metal  stopcock,  so  that  the  fluid  can  be  sucked  uj) 

*  The  simplest  and  hes,t  tourniquet  is  some  rubber  tubing,  which  should  be  wound  tightly 
around  the  arm  and  the  two  ends  fixed  with  pressure  foiceps,  which  can  be  removed  without 
disturbing  the  limb. 


METHODS   OF   USING    AXTI-SYPHILITIC   DRUGS. 


343 


from  the  vessel,  and  injected  directly  into  the  vein.  The  needle  has  also  a  plate 
at  its  base  npon  which  a  finger  can  rest  to  keep  it  steady.  The  one  disadvantage 
of  this  syringe  is,  that  the  whole  apparatus  is  rigid,  therefore  the  slightest  movement 
of  the  syringe  may  be  sufficient  to  dislodge  the  needle. 

To  overcome  this  difficulty  Allen  &  Hanbury  have  constructed  for  me  a  needle 
which  is  Ij  inches  in  length,  behind  which  is  a  slightly  concave  metal  plate,  which 
rests  on  the  arm,  and  which  may  be  fixed  by  a  piece  of  tape  which  runs  under  a 
metal  bridge,  and  is  tied  under  the  arm  should  it  be  required.     This  needle  is  fixed 


Ki-i;5|'!«'!'i'^l'i'l'M*l'['''W'':ir 


^^\  Scale   £  ' 

itcDona^li's  Syringe 


The  same  in  use 


by  means  of  a  bayonet-catch  to  the  three-way  stopcock ;  but  connection  between 
the  needle  and  the  bayonet-catch  is  made  by  a  piece  of  thick  rubber  tubing,  so  that 
every  movement  of  the  stopcock  or  sninge  behind  is  broken  by  this  flexible 
connection,  and  does  not  affect  the  needle. 

The  all-glass  syringe,  which  should  hold  20  or  30  c.c,  fits  on  to  the  stopcock 
by  means  of  a  piece  of  stout  rubber  tubing,  instead  of  being  inserted  into  a  metal 
tube,  which  may  not  fit  every  spinge.  The  best  syringes  are  Luer's ;  they  are 
of  French  manufacture,  but  can  be  ordered  in  London  through  Allen  &  Hanbury. 
Both  the  English  and  the  German  makes  are  bad  fits,  and  do  not  withstand  frequent 
boilings. 

The  s}'Tinge  is  first  filled  with  saline  solution,  and  all  air  is  expressed  both 


344  THE   BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

through  the  tubing  and  the  needle ;  then  the  needle  is  inserted  into  the  vein, 
with  the  stopcock  open,  being  guided  and  held  by  the  metal  bridge  above  it. 
If  the  vein  has  been  pierced,  and  this  can  at  once  be  told  by  touch,  or  by  blood 
flowing  back  into  the  syringe,  the  tourniquet  should  be  removed  and  some 
saline  injected.  If  the  cannula  is  not  completely  in  the  vein,  the  sahne  will 
produce  infiltration ;  this  being  the  case,  the  needle  should  be  withdrawn  and 
another  vein  chosen,  as  it  is  most  important  to  prevent  any  of  the  "  606  " 
solution  getting  under  the  skin,  as  considerable  pain  is  caused  thereby.  If 
much  escapes,  there  will  be  painful  induration  and  oedema  of  the  arm,  and  it 
takes  weeks  to  disappear.  ^^Tien  the  solution  has  all  been  injected,  some  saline 
should  finally  be  used  to  avoid  leakage  of  a  drop  or  two  of  "  606,"  this  is  done 
by  transferring  the  tubing  from  the  "  606  "  vessel  to  the  one  containing  saline. 
If,  during  the  injection,  the  needle  slips,  and  some  of  the  solution  escapes — the 
patient  complaining  at  the  same  moment  of  a  burning  sensation — one  shoidd 
immediately  take  the  needle  out,  apply  a  tourniquet  to  the  arm,  and  allow  the  vein 
to  bleed,  which  will  often  prevent  infiltration  forming.  If  the  injection  is  skilfully 
done,  the  patient  has  no  pain.  Under  no  circumstances  must  the  preparation  be 
injected  in  a  concentrated  form,  and  great  care  should  be  taken  not  to  inject  it  too 
quickly. 

D. — Intravenous  Injection  of  Neo-salvarsan. 

Instead  of  sahne,  pure  distilled  water  is  used,  in  which  the  powder  is  simply 
dissolved  without  the  addition  of  any  other  substance,  in  the  proportion  of  0 '  1  grm. 
neo-salvarsan  to  35  c.c.  distilled  water.  The  temperature  of  the  water  to  be 
injected,  should  never  be  above  that  of  the  room.  In  other  words,  the  water 
never  requires  heating.  The  resulting  solution  is  hj-potonic,  which  might  at 
first  sight  seem  to  be  a  disadvantage,  but  it  causes  no  disturbance  when  it 
gets  into  the  general  circulation.  The  urine  passed  after  the  injection  is  often 
highly  coloured,  owing  to  the  excess  of  pigments,  which  have  resulted  from  the 
breaking  down  of  some  of  the  red  blood  corpuscles  ;  but  no  hismoglobinuria  or 
other  signs  and  symptoms,  which  might  result  from  an  haemolysis,  are  to  be  met 
with. 

Concentrated  intravenous  injections  of  neo-salvarsan  can  be  given,  but  they 
have  the  disadvantage  of  producing  more  immediate  unpleasant  symptoms,  such  as 
headache,  sickness,  a  rise  of  temperature,  etc.,  and  a  local  thrombosis  of  the  vein 
is  more  apt  to  arise. 

The  powder  is  dissolved  in  10  to  30  c.c.  of  pure  distilled  water,  and  then  injected 
directly  into  the  vein.     It  does  not  appear  to  matter  how  much  water  is  used. 


METHODS   OF   USING    ANTI-SYPHILITIC    DRUGS.  345 

Another  raetliod  is  to  put  the  powder  into  the  spinge,  insert  the  needle  whicli 
is  attached  to  the  syringe  into  the  vein,  and  let  the  blood  which  flows  back  into  the 
sjTinge  dissolve  the  salt.  When  the  powder  is  dissolved,  the  blood  containing  the 
neo-salvarsan  in  solution  is  re-injected  into  the  vein.  AATien  the  solution  injected 
is  below  the  body  temperature,  the  median  basiUc  vein,  should  be  used  in  preference 
to  the  median  cephahc,  since  the  distension  of  the  vein  and  the  cool  solution  running 
along  it,  irritates  the  circumflex  nerve  and  causes  considerable  pain,  in  the  region 
of  the  shoulder. 

There  are  now  two  points  to  be  considered  :  One  is,  whether  the  intramuscular 
route  is  preferable  to  the  intravenous,  or  vice  versa ;  and  the  other  is,  ^\hether 
salvarsan  is  better  than  neo-salvarsan,  or  ince  versa. 

I  am  very  stronglj^  of  the  opinion  myself  that  the  intravenous  administration 
is  better,  in  every  way,  than  the  intramuscular.  The  drug  is  excreted  more  quickly 
when  given  intravenously,  and  one  knows  when  it  is  safe  to  repeat  the  injections. 
When  given  intramuscularly,  one  cannot  tell  how  much  has  been  absorbed,  how 
much  has  been  excreted,  and  therefore  when  it  is  safe  to  give  the  next  injection. 

With  these  new  arsenical  preparations,  it  appears  that,  in  order  to  get  the 
best  results,  it  is  necessary  to  repeat  the  Injections  at  the  shortest  possible  intervals, 
which  can  only  be  done  when  the  intravenous  route  is  chosen.  When  the  drug  is 
injected  intravenously,  more  of  it  reaches  the  spot  at  which  it  is  required  than  when 
given  intramuscularly,  and,  moreover,  it  reaches  the  lesion  more  quickly. 

When  a  drug  is  slowly  absorbed,  as  it  is  when  given  intramuscularly,  the 
parasites  against  which  it  is  directed,  quickly  become  immune  to  its  action.  With 
these  new  arsenical  preparations  this  is  especially  noticeable.  The  patient  suffers 
very  much  less  inconvenience  when  the  drug  is  prescribed  via  the  veins.  These, 
and  other  minor  points  which  could  be  brought  forward,  clearly  indicate  that  the 
intravenous  route  is  the  route  for  choice. 

Concerning  the  advantages  of  one  drug  over  the  other,  more  than  the  mere 
potency  has  to  be  considered. 

Injection  for  injection,  there  is  no  doubt  but  that  salvarsan  is  more  potent 
than  neo-salvarsan ;  but  the  difference  is  becoming  less  and  less  marked,  as  the 
salvarsan  now  supplied  does  not  appear  to  me  to  be  as  strong  as  that  which  was  in 
use  when  neo-salvarsan  first  came  in. 

Salvarsan  causes  more  immediate  disturbance  than  neo-salvarsan,  therefore  the 
intervals  between  the  injections  usually  have  to  be  longer,  and  the  drug  is  not  so 
suitable  for  out-patient  work.  Neo-salvarsan  can  be  given  every  four  days,  and  to  out- 
patients with  impunity  ;  and  since  as  good  results  can  be  obtained  with  neo-salvarsan 
as  with  salvarsan,  provided  a  few  more  injections  are  given,  it  will  be  seen  that  the 


346  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF    SYPHILIS. 

advantages  of  neo-salvarsan  strongly  outweigh  the  disadvantages  of  salvarsan. 
Owing  largely  to  the  fact  that  the  patients  need  not  go  into  a  nursing  home,  and 
as  equally  good  results  may  be  obtained  with  the  two  drugs,  I  almost  invariably 
use  the  neo-salvarsan  now. 

E. — Infmtkecal  Injection  of  Salvarsanised  Serum. 

The  method  to  be  now  described  is  that  which  has  been  elaborated  by  Homer 
Swift  and  Elhs.^  The  patient  is  first  given  an  intravenous  injection  of  salvarsan 
or  neo-salvarsan.  One  to  two  hours  later,  about  50  c.c.  of  blood  are  withdrawn 
from  a  vein  into  a  sterile  tube.  The  tube  must  be  shaken  occasionally,  to  prevent 
the  clot  from  sticking  to  its  sides,  which  prevents  the  separation  of  the  serum. 
WTien  the  serum  has  separated  out,  the  tube  is  placed  in  an  incubator  at  57°  C, 
for  one  hour.  The  following  day,  the  serum  is  collected,  mixed  with  an  equal 
quantity  of  saUne  (about  25  c.c.  of  each),  and,  after  an  approximately  corresponding 
amount  of  cerebro-spinal  fluid  has  been  withdrawn,  the  diluted  serum  is  injected  into 
the  canal.     (For  the  details  of  performing  a  lumbar  puncture,  vide  Chapter  XXII.) 

The  best  needles  for  performing  lumbar  puncture  are  Barker's,  and  both  Messrs. 
Maw,  Son  &  Sons,  and  Allen  &  Hanbury  have  constructed  a  mount  for  my  three-way 
s)T.'inge,  which  makes  the  injection  of  salvarsanised  serum  a  very  simple  matter. 

After  the  operation,  the  patient  is  placed  with  his  head  low  down,  and  the 
bottom  of  the  bed  is  well  raised,  so  as  to  allow  the  fluid  to  gravitate  towards  the 
brain. 

Many  observers^  have  attempted  to  inject  salvarsan  and  neo-salvarsan  dii'ectly 
into  the  spinal  canal,  and  also,  in  cases  of  degenerative  encephalitis,  into  the  lateral 
ventricles.  The  general  consensus  of  opinion  is  that,  the  danger  of  toxic  symptoms 
supervening  contraindicates  such  measm-es  being  adopted. 

The  very  small  doses  of  the  drug  which  can  in  this  way  be  injected,  must,  even 
by  the  enthusiasts,  be  considered  msufiicient  to  be  curative,  and  the  good  results 
which  have  been  obtained,  could  have  been  equally  well  achieved  with  the  salvar- 
sanised serum.  We  have  yet  to  learn  the  future  of  the  cases  which  have  been 
treated  with  salvarsanised  serum,  since  it  is  mainly  on  theoretical  grounds  that  its 
administration  is  based.  There  is  no  doubt  that  it  does  good  in  meningeal  lesions, 
but  whether  it  is  only  palliative  or  curative,  we  have  yet  to  learn. 

The  intrathecal  injections  have  unfortunately  two  very  great  disad- 
vantages. One  is,  that  the  symptoms  are  usually  aggravated  by  the  first 
two  injections — this  is  true  only  of  those  that  accompany  degenerative 
lesions — and  the  other  is,  that  patients  do  so  object  to  repeated  lumbar  puncture, 
that  they  often  refuse  to  continue  the  treatment.     If  the  treatment  is  discontinued, 


METHODS   OF    USING    ANTI- SYPHILITIC    DRUGS.  347 

the  patient's  condition  is  veiy  often  permanently  aggravated.  I  think  this  rule 
may  be  safely  made  in  the  case  of  nerve  syphihs,  that  it  is  useless,  and  often 
harmful,  to  prescribe  treatment,  unless  it  is  intended  to  be  drastic,  or,  in  other 
■words,  sufficient  to  render  the  cerebro-spinal  fluid  approximately  normal. 

I  would  here  draw  the  reader's  attention  to  the  fact  that  the  globuUn  test 
may  fail,  after  the  first  or  second  injection  of  salvarsanised  serum.  By  the  unwary, 
this  is  assumed  to  show  that  one  or  two  injections  have  cured  the  patient.  Not 
only  may  the  globulin  disappear,  but  the  Wassermann  reaction  may  become 
negative.  Exactly  the  same  thing  may  happen  with  the  serum  of  a  late  case  of 
s}'philis  (vide  Chapter  XI). 

The  decrease  in  globulin,  and  the  negative  Wassermann  reaction  is  simply  due 
to  the  fact  that  the  existing  lipoid -globulin  particles  become  hydrolysed  when 
salvarsan  or  salvarsanised  serum  is  first  given.  This  is  the  explanation  of  the  so- 
called  negative  phase.  Improvement  follows  only  when  the  negative  phase  has 
passed  off,  and  this  is  due  to  the  destruction  of  the  old  Hpoid -globulin  particles 
and  the  formation  of  new  ones.  It  is,  moreover,  an  indication  for  further  treat- 
ment, not  for  a  stoppage  of  the  same. 

Other  Arsenical  Compounds. 

As  the  French  laws  deahng  with  the  patenting  of  drugs  differ  from  the  Enghsh 
ones,  and  as  their  chemists  show  more  enterprise  than  ours,  not  only  have  salvarsan 
and  neo-salvarsan  been  prepared  for  some  considerable  time  in  France,  but  also 
other  similar  products  have  seen  daylight.  Mouneyrat  has  prepared  what  he  calls 
"  1116  "  (Galyl)  and  "  1151  "  (Ludyl).  Neither  of  these  has  any  advantage  over 
neo-salvarsan,  and  it  would  appear,  from  the  small  experience  which  observers  have 
had  with  them,  that  they  are  not  quite  so  potent.  There  is  no  doubt,  but  that, 
within  a  few  years,  the  market  will  be  flooded  with  synthetic  drugs,  which  will 
differ  little  from  the  original  salvarsan,  although  each  will  be  said  to  be  a  distinct 
improvement.  Chemotherapy  is  a  very  distinct  advance  upon  our  old  empirical 
meth6d  of  prescribing  drugs,  but  it  must  be  remembered  that  the  science  is  in  its 
earliest  infancy,  and  that  even  the  foundation  upon  which  salvarsan  was  built,  has 
turned  out  to  be  unsound. 

Theoretically,  Ehrlich's  conceptions  were  brilliant,  but  unfortunately,  having 
no  first-hand  knowledge  of  syphihs,  he  was  obhged  to  rest  upon  the  knowledge 
of  others,  whose  work  and  conceptions  now  appear  to  be  wrong.  The  Spirochaeta 
pallida  is  not  the  cause  of  s}'philis,  and  its  destruction  does  not  result  in  the  cure 
of  the  disease.  Ehrhch's  work  with  salvarsan  was  only  in  connection  with  the 
Sjyirochaeta  pallida  ;  the  other  phases  of  the  Leucocytozoon  syphilidis  were  unknown 


3i8  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF    SYPHILIS. 

to  him.  Ehrlich  also  was  not  familiar  Avith  the  chemical  points  which  have  since 
been  worked  out,  in  connection  with  the  organism  and  the  host's  serum,  hence 
the  description  of  the  action  of  salvarsan  which  Ehrhch  gives,  is  only  a  fraction 
of  its  manifold  action,  which  naturally  could  not  be  discerned,  until  the  other  facts 
just  mentioned  had  been  discovered. 

Salvarsan  will  certainly  be  the  starting  point  of  many  valuable  future  dis- 
coveries, and,  even  so  far  as  syphilis  is  concerned,  it  is  highly  probable  that  it  can 
and  will  be  improved  upon.  For  future  research  in  this  direction  to  be  productive, 
special  thought  will  have  to  be  paid  to  the  spore,  and  not  to  the  SpirocJiaeta  pallida, 
and  as,  in  my  opinion,  the  chemical  nature  of  the  spore  will  defy  any  direct  attack 
against  it,  the  indirect  action  of  the  proposed  synthetic  compounds  will  have  to  be 
taken  into  main  consideration — not  their  du'ect  action,  the  only  action  which  has 
heretofore  received  any  recognition  whatsoever. 

The  action  of  a  drug  can  only  be  adequately  gauged  by  clinical  observation, 
hence  my  readers  will  be  well  advised  to  adhere  to  the  drugs  which  have  so  far 
passed  the  test  of  time,  before  rushing  to  employ  any  new  modification  or  so-called 
improvement,  until  it  really  has  been  proved  by  experience  to  be  an  improvement. 
So  much  work  has  been  done  with  the  idea  of  gauging  how  many  injections  of 
salvarsan  should  be  given,  the  intervals  at  which  they  should  be  given,  etc.,  that 
the  phases  we  have  gone  through  have  been  various,  and  existing  opinions  are 
legion.  The  only  disadvantage  that  such  a  state  of  affairs  has,  is  a  disadvantage 
to  which  only  the  patient  has  to  submit,  and  he  is  the  individual  for  whom  the  drug 
was  manufactured. 

Antimony. 

As  an  alternative,  antimony  is  a  useful  drug  to  have  up  one's  sleeve.  I  prefer 
intravenous  injections,  as  intramuscular  injections  are  apt  to  be  very  painful.  I 
have  not  sampled  all  the  antimony  products  which  have,  from  time  to  time,  been 
advocated,  therefore  I  cannot  say  that  any  one  preparation  is  any  better  than  any 
other.  As  no  preparation  of  antimony  is  as  powerful  as  salvarsan,  and  therefore 
is  not  one's  sheet  anchor,  but  is  used  only  as  an  alternative,  it  does  not  matter  very 
much  which  preparation  is  employed.  For  intramuscular  injections  I  have  used 
antiluetin  (bitartrate-potassium-ammonium-antimony  oxide).  The  salt  is  readily 
soluble  in  water,  and  is  best  put  up  in  ampoules  containing  1  c.c.  according  to  the 
following  formula  : — 

H.  Antiluetin 0  •  025-0  •  1  grm. 

Cocain.  hydrochlor 0" 025  grm. 

Thymol q.s. 

Aq.  distill.  1  c.c. 


METHODS    OF   USING    ANTI-SYPHILITIC    DRUtiS.  349 

A  course  should  consist  of  twelve  injections,  given  daily  or  every  other  day, 
beginning  with  0"025  grin,  and  ending  up  with  0'2  grni. 

For  intravenous  injections  I  employ  either  tartar  emetic  or  antiluetin. 

If  the  former,  I  have  ampoules  made  up  containing  1  c.c.  of  distilled  water 
and  1  to  Ij  grains  of  tartar  emetic.  I  place  the  contents  of  one  ampoule  in 
5  ozs.  of  distilled  water,  and  give  ten  injections  in  all,  twice  or  three  times  a  week. 

Antiluetin  is  used  in  the  same  way,  and  for  each  injection  0'025  to  0'05  grm. 
is  employed,  without  the  cocaine. 

Toxic  symptoms  occurring  after  antimony  injections  are  much  like  those 
occurring  after  intravenous  injections  of  mercury,  but  even  slight  symptoms  are 
ver}'  rare. 

Although  not  a  venereal  disease,  I  should  like  to  mention  here  that  I  have 
had  great  success  in  treating  cases  of  bilharzia  with  intravenous  injections  of 
antimony.     In  my  experience,  salvarsan  is  of  no  use  in  this  complaint. 


Mercury. 

A. — Intravenous  Injection. 

A  very  good  way  of  giving  mercury  is  intravenously,  and  the  two  best  salts  are 
the  cyanide  and  the  bichloride. 

If  the  cyanide  is  going  to  be  used,  a  stock  solution  of  1  in  100  should  be  made, 
and  0'5  c.c.  to  1'5  c.c.  of  this  solution  may  be  injected  daily  or  every  other  day. 
A  course  usually  consists  of  ten  to  twelve  injections. 

If  the  bichloride  of  mercury  is  preferred,  ampoides  of  1  c.c.  should  be  made 
up,  each  containing  \  gr.  of  the  salt.  A  course  should  consist  of  ten  to  twelve 
injections,  given  twice  or  three  times  a  week.  For  the  first  three  doses  only 
0'5  c.c.  should  be  used,  and  for  the  remaining  doses  1  c.c. 

Instead  of  using  the  solutions  concentrated,  I  think  it  is  best  to  put  the 
contents  of  an  ampoule  into  a  syringe  holding  30  c.c.  of  pure  distilled  water. 
Diluting  the  solution  diminishes  the  likelihood  of  producing  local  thrombosis,  and 
also  of  toxic  symptoms  arising.  I  prefer  myself  to  use  as  much  as  5  ozs.  of  water. 
Toxic  symptoms  may  follow  intravenous  injections  of  mercury,  but  they  are  of 
little  note ;  the  commonest  are  abdominal  pains  and  diarrhoea.  A  pecidiar 
sensation  in  the  throat  is  sometimes  complained  of,  and  momentary  congestion  of 
the  face  and  difficulty  of  breathing  may  now  and  again  occur,  almost  immediately 
after  the  injection. 


350  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

B. — Intramuscular  Injection. 

There  is  a  legion  of  preparations  of  mercury  for  intramuscular  use,  and  they 
can  be  divided  into  two  classes  :  (a)  soluble  ;  and  (6)  insoluble.  There  is  absolute!}'  no 
doubt  but  that  the  insoluble  salts  are  far  more  efficacious  than  the  soluble  ones.  So 
far  as  the  insoluble  salts  are  concerned,  one's  choice  Ues  between  three.  One  of  these 
— and  that  is  calomel — can,  from  my  experience,  be  deleted,  since,  although  it  is 
perhaps  more  potent  than  grey  oil,  its  administration  is  unfortunately  so  frequently 
very  painful,  that  patients  get  frightened  away  from  all  kinds  of  intramuscular 
injections.  Moreover,  however  careful  one  is,  abscess  formation  is  more  hable 
to  follow  intramuscular  injections  of  calomel  than  any  other  preparation  I 
know. 

That  leaves  us  with  two  preparations,  and  the  choice  between  them  will  rest 
upon  whether  a  quicker  and  a  less  potent  action,  or  a  slower  and  a  more  potent 
action  is  required. 

Before  the  salvarsan  era,  it  was  often  necessary  to  get  rid  of  the  lesion  as  quickly 
as  possible ;  consequently,  one  preferred  to  use  a  preparation  which  was  very  quickly 
absorbed  to  one  which  was  slowly  absorbed,  although  the  potency  of  the  latter  was 
greater  than  that  of  the  former.  With  the  exception  of  the  insoluble  salts,  which 
are  naturally  rapidly  abSo"rbed,  but  whose  action,  even  in  the  maximum  doses,  does 
not  amount  to  very  much,  no  preparation  is  so  suitable  as  the  salicylate  of  mercury, 
because  not  only  is  it  quickly  absorbed,  but  its  action  exceeds  the  action  of 
the  maximum  doses  of  the  insoluble  salts.  The  best  preparation  for  injection  is 
1  c.c.  of  a  10  per  cent,  emulsion  of  mercury  salicylate  in  liquid  paraffin.  Either 
1  c.c.  of  this  emulsion  can  be  injected  weekly,  or  0"5  c.c.  can  be  prescribed  twice 
a  week. 

As  salvarsan  has  rendered  the  question  of  the  rate  of  absorption  of  the  mer- 
curial preparation  of  no  account,  one  need'  only  consider  the  question  of  the 
ejB&cacy. 

In  my  opinion,  the  best  mercmial  preparation,  and  the  one  I  now  always  use 
myself,  is  Adam's  Cream.  It  is  a  grey  oil  preparation,  which  is  liquid  at  the  ordinary 
temperature,  and  therefore  does  not  have  to  be  heated ;  its  bulk  is  small  and, 
therefore,  practically  painless. 

The  grey  oils  in  previous  use  have  been-  unsatisfactory,  because  they  required 
heating.  Now  the  action  of  heat  is  to  cause  the  globules  of  mercury  to  conglomerate, 
so  that,  in  time,  most  of  the  metal  is  at  the  bottom  of  the  bottle,  with  the  result  that 
the  first  injections  contain  less  mercury  than  the  last.  Their  bulk  was  always 
great,  consequently  the  patients  frequently  complained  of  pain. 


METHODS   OF   USING    ANTI- SYPHILITIC   DRUGS.  351 

The  following  is  the  prescription  of  Adam's  Cream,   and  it    is  prepared  for 
me  by  Squire  &  Sons,  413,  Oxford  Street,  London,  W.  : — 

R  Hydrarg.  20  parts. 

Anhjalrous  lanol.  . .         . .         . .         30      ,, 

Chlorbutol •         . .         . .  2      „ 

All  aa  by  weight. 
Liq.  parafSn  to  100  by  measure. 
5  minims  =  Hg.  1  grain. 
Inject  5-10)11  weekly. 
The  injections  should  be  made  into  the  gluteal  muscles,   the  scajjular  muscles, 
or  into  the  latissimus  dorsi  muscle  below  the  ribs  or  the  angle  of  the  scapula.     If 
the  gluteal  region  is  chosen,  the  injection  should  be  made  round  about  the  upper 
and  outer  margin  of  the  main  fleshy  mass.     In  the  scapular  region,  the  needle 
should  be  inserted  from  above  downwards,  deep  into  the  muscles,   about  midway 
between  the  posterior  border  of    the  scapular  and  the  spinous  processes  of  the 
vertebrae.  The  best  syringe  to  use  is  the  Eecord  syringe  for  intramuscular  injections  of 
mercury,  supplied  by  the  Holborn  Surgical  Instrument  Co.,  26  Thavies  Inn,  Holborn. 
The  laws  of  asepsis  having  been  strictly  complied  with,  plunge    the  needle  in 
quickly  for  2|  to  3  ins.,  but  avoid  touching  the  bone.      Remove  the  syringe  from 
the  needle  to  see  if  any  blood  flows  from  it.     If  so,  withdraw  and  plunge  again,  as 
the  presence  of  blood  shows  that  a  vein  has  been  entered,  with  obvious  danger  of 
embolism.      Inject   very   slowly,   then   withdraw   quickly,  while  pressing   the   skin 
around  the  pimcture,  to  prevent  bleeding.     Rub  the  part  well  for  a  few  minutes, 
and  send  your  patient  for  a  brisk  walk. 

As  the  soluble  preparations  are  very  seldom  called  for  nowadays  it  is  not 
necessary  to  mention  all  that  have  from  time  to  time  been  used.  If  I  ever  use  a 
soluble  salt,  I  always  prescribe  enesol. 

Enesol  is  a  useful  mercurial  preparation,  especially  in  those  cases  to  which 
salvarsan  cannot  be  given,  and  in  which  it  is  wished  to  get  the  patient  under  the 
influence  of  mercury  as  quickly  as  possible.  Enesol  is  a  saHcyl-arsenate  of  mercury, 
readily  soluble  in  water,  and  is  put  up  in  ampoules  of  1  c.c.  In  each  ampoule  there 
is  O'OllS  grm.  of  mercury  and  0'0043  grm.  of  arsenic. 

1  to  3  c.c.  may  be  injected  intramuscidarly  daily  or  every  other  day,  until  a 
marked  improvement  has  taken  place ;  or  the  salt  may  be  injected  intravenously. 
The  latter  route  being  the  better  of  the  two,  1  to  4  c.c,  in  5  ozs.  of  distilled  water, 
may  be  injected  intravenously  every  second  day  or  twice  a  week,  until  twelve 
injections  have  been  given. 

A  mercurial  preparation,  which  is  sometimes  useful  in  checking  the  lightning 

z 


352 


THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   SYPHILIS. 


pains  of  degenerative  myelitis  when  other  preparations  have  failed,  is  the  so-called 
Hirsch's  injection.  The  solution  contains  1  per  cent,  oxycyanide  of  mercury  and 
0"4  per  cent,  acoine ;  1  to  3  c.c.  are  injected  intramuscularly  daily  or  every  other 
day,  until  30  c.c.  have  been  used.  This  preparation  does  undoubtedly,  in  some 
cases,  give  reUef,  but,  in  my  experience,  the  pains  soon  recur  when  the  action  of 
the  drug  has  worn  off.  Acoine  is  a  white  crystalline  powder,  and  is  the  name  applied 
to  the  local  anaesthetic  di-para-anisyl-monophenetyl-guanidine  hydrochloride,  for 
which  the  British  Pharmaceutical  Codex,  1911,  gives  the  short  name  guanicaine. 

C. — Inunction. 

There  can  be  no  doubt  that  the  best  way  of  administering  mercury  is  by 
inunction,  but  unfortunately  this  method  is  valueless,  unless  it  is  carried  out  by 
a  trained  rubber. 

Inunction  is  one  of  the  oldest  methods  of  administration.  It  does  not  upset 
digestion,  it  gets  the  patient  under  the  influence  of  mercury  more  quickly  than  oral 
administration,  and  it  is  easily  regulated.  It  is  best  to  use  either  unguent,  cinereum, 
which  consists  of  one  part  Hg.  with  two  of  lanoline  and  ung.  simplex  ;  or  mercury 
resorbin  1  to  2.  The  adult  dose  of  ointment  is  from  1  to  7  drachms  ;  children  take 
from  J  to  1  drachm.  The  following  is  a  good  order  of  inunction,  one  hour  a  day 
being  given  to  the  work  : — 


2nd    „ 

. .     Both  legs. 

3rd     , 

. .     Both  arms. 

4th 

. .     Chest  and  abdomen. 

5th     , 

. .     Back. 

6th    „ 

. .     Hot  bath. 

7th    , 

. .     Re-commence  as  on  1st 

The  inguinal  region,  nipples,  and  all  hairy  parts  must  be  shunned,  as  acute 
pustular  eczema  may  arise.  The  flat  part  of  the  palm  should  be  used  for  rubbing, 
and  a  fair  even  pressure  maintained.  Inunction  is  contraiudicated  by  eczema, 
prurigo,  and  psoriasis.  If  the  patient  has  rubbed  himself,  or  has  been  rubbed, 
effectively,  his  skin — ^when  all  superfluous  ointment  has  been  removed  %dth  a  towel 
— should  show  a  number  of  black  dots  where  the  mercury  has  penetrated  the  pores. 
Mercury  is  in  part  absorbed  through  the  pores  of  the  skin,  and  in  part  evaporated 
by  the  heat  of  friction.  The  vapour  so  given  off  is  inhaled,  and  inhaled  mercurial 
vapour  speedily  gives  rise  to  stomatitis.  In  a  ward  where  syphilitic  patients  are 
using  inunctions,  it  is  not  rare  for  non-s^'philitic  ones  to  get  mercurial  stomatitis 
from  evaporation  and  inhalation.      It  is,  therefore,  well  that  inunction  be  done 


METHODS   OF   USING   ANTI-SYPHILITIC    DRUGS.  353 

in  the  early  morning,  in  a  well  ventilated  room  in  which  the  patient  is  not  going  to 
remain,  and  that  the  mouth  be  rinsed  out  several  times  with  pot.  chlor.  while 
rubbing.  A  patient  shoidd  not  keep  to  his  room  except  in  cold  and  windy  weather, 
and  his  clothes  should  not  be  too  warm.  Menstruation  is  no  bar  to  continuing 
inunction.     A  course  of  inunctions  should  consist  of  thirty  to  forty  rubbings. 

A  useful  adjunct  to  mercury  is  sulphur.  Sulphur,  either  in  the  form  of  baths 
or  the  drinking  of  waters  which  contain  it,  is  always  useful  when  a  patient  is 
undergoing  mercurial  treatment,  be  it  in  whatever  form  it  is  prescribed. 

D.— Baths. 
Baths  are  indicated  in  cases  of  ulcerative  skin  lesions  which  make  inunctions 
impossible.  They  serve  two  purposes,  for  the  sublimate  is  absorbed  from  the  raw 
surfaces,  and  also  acts  as  a  local  treatment  to  them.  10  to  30  grs.  of  sublimate 
are  dissolved  in  a  hot  bath,  in  which  the  patient  remains  for  half  an  hour,  tem- 
perature being  kept  at  about  95°  F.  by  the  addition  of  hot  water  or  by  a  warming 
apparatus.     A  bath  is  given  daily,  and  the  patient  is  kept  in  bed  for  one  hour  after  it. 

E. — Fumigation. 
Fumigation  is  only  mentioned  to  be    deprecated,  since  mercurialism  is   almost 
unavoidable. 

F. — Impregnation. 
Impregnating  the  underclothing  with  mercury,  or  spreading  emplast.  cinereum 
over  a  large  surface  of  the  body  is  quite  a  good  method  of  treating  infantile  cases. 

G. — Supjyositories. 
Mercurial  suppositories  can   sometimes  be  employed  with  advantage,   if  an 
alternative  method  of  prescribing  the  drug  is  required. 
A  suppository  should  be  made  up  as  follows  : — 

B:  Hydrarg.  salicylatis      . .         . .         . .         gr.  |-iij 

01.  theobromi     . .         . .         . .         . .         q.  s. 

One  should  be  inserted  every  night  just  before  going  to  bed,  until  either  the 
rectiun  begins  to  get  sore,  or  the  gums  begin  to  get  tender.  If  the  suppositories 
cause  much  local  pain,  this  may  be  obviated  by  adding  a  little  cocaine  to  each. 

In  tropical  countries  a  httle  white  wax  has  to  be  added,  owing  to  the  low 
melting  point  of  the  ol.  theobromi. 

H. — Internal. 
Internal  treatment  has  the  great  disadvantage  that,  by  irritation  of  the  mucous 
membrane,  digestion  is  upset.     We  also  know  not    how  much  mercury  is  being 

z2 


354  THE   BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

assimilated,  because  we  know  not  how  much  is  being  passed  per  viam  naturalem.  The 
dose,  therefore,  has  to  be  somewhat  greater,  so  as  to  be  on  the  safe  side.  It  is  useful 
in  late  stages  of  the  disease,  where  it  is  not  necessary  to  get  the  patient  quickly 
under  the  influence  of  mercury,  and  as  a  change  from  inunctions  and  injections. 
Its  great  sphere  of  usefulness  is  in  sucklings,  in  whom  iimnctions  are  generally 
followed  by  eczema,  but  who  stand  J  gr.  of  hydr.  c  cret.  twice  a  day  well.  For 
adults,  Hutchinson's  pill  is  largely  used  in  England  : — 

R  Hydrarg.  c  cret. 

Pulv.  ipecac,  co.  . .         . .         . .         aa  gr.  j 

One  pill  to  be  taken  three  times  a  day,  after  meals. 

Of  greater  utility  is  Ricord's  pill,  which  contains  iodine  : — 

R  Hydrarg.  iod.  virid.       . .  . .  . .  gr.  | 

Ext.  opii.  . .         . .         . .  . .  gr.  J 

Adjuvant.  . .         . .         . .  . .  ci.  s. 

One  pill  to  be  taken  twice  a  day,  after  meals. 

The  following  formula  is  commendable,  in  that  the  mercury  is  in  a  form  less 
likely  to  injure  the  mucous  membrane,  so  upsetting  digestion  : — 

R  Hydrarg.  tannici  oxydulat.      . .         . .  gr.  j 

Ext.  opii.  . .  . .  . .  . .  gr.  J 

Adjuvant.  . .  . .  .  .  .  .  q.  s. 

One  pill  to  be  taken  three  times  a  day,  after  meals. 

Mercurial  stomatitis  is  the  complication  which  most  usually  besets  us.  It 
is  also  the  most  valuable  guide  b}'  which  to  regulate  the  dose  of  mercury.  Stomatitis 
must  be  solely  dependent  upon  the  teeth,  for  the  toothless  at  both  ends  of  life's  ladder 
are  never  affected.  If  the  teeth  be  well  looked  to — cavities  filled,  tartar  scraped, 
and  stumps  removed — ^before  commencing  treatment,  and  well  looked  after  during 
treatment,  stomatitis  will  seldom  become  severe.  The  care  of  the  teeth  during 
treatment  consists  in  absolute  abstinence  from  both  alcohol  and  tobacco,  and  the 
brisk  use  of  the  toothbrush  after  each  and  every  meal,  followed  by  an  astringent 
mouthwash,  as  pot.  chlor.  gr.  x  ad  ,^j  or : — 

R  Acid  carbol.        . .         . .         . .         . .         gr.  x 

Spir.  vini  rect. 

Aq.  dist.  . .         . .         . .         . .         aa  ad.  3j 

Put  a  teaspoonful  into  a  tumbler  of  warm  water. 


METHODS   OF   USING    ANTI-SYPHILITIC    DRUGS.  355 

Should  the  gums  bleed,  the  following  should  be  painted  on  : — 

H  Tint.  gall. 
Tinct.  rhatan. 
Tinct.  myrrh.,  aeq.  part. 

Or  simply  ghjcerinum  acid,  tannici.  Should  pus  or  ulceration  be  present,  paint 
twice  daily  with  tinct.  iod.  or  perhydrol. 

A  slight  stomatitis  is  a  valuable  guide  to  the  degree  of  mercurialism  attained. 
It  should  be  our  aim  to  press  mercurial  treatment  to  the  exact  point  at  which 
slight  stomatitis — a  trace  of  salivation,  with  slight  swelhng  of  the  gums,  a  diminution 
of  the  papillae  till  the  free  edge  of  the  gums  forms  a  nearly  straight  hne — is  reached 
and  maintained. 

Mercurial  treatment  must  be  intermittent,  because  of  the  danger  of  mer- 
curialism. In  whatever  form  mercury  enters  the  system,  it  is  eliminated  as  a 
sulphide  via  bowels,  kidneys,  and  saliva.  It  is  excreted  very  slowly,  and  therefore 
accumulates  and  becomes  fixed  in  the  system.  It  is  only  the  excreted  portion 
which  has  had  any  action  on  the  virus.  The  fixed  portion  is  harmful,  and  is  the 
cause  of  the  chain  of  symptoms  known  as  mercurialism.  These  generally  begin 
with  fcetor  of  breath  and  soreness  of  gums,  followed  by  a  metallic  taste  in  the 
mouth,  swelling,  softness,  bleeding,  and  ulceration  of  gums.  The  salivary  glands 
become  enlarged  and  tender,  causing  increased  salivation ;  the  tongue  swells, 
teeth  become  loose,  and  ulceration  of  the  mucous  membrane  of  the  mouth,  even 
necrosis  of  the  jaw,  may  foUow ;  anaemia  becomes  marked,  the  blood  becomes 
watery,  and  fails  to  coagulate,  thereby  increasing  the  liability  to  haemorrhage. 
Now,  patients  do  not  like  these  symptoms,  and  it  is  best  to  avoid  them  by  inter- 
mitting the  doses  of  mercury  and  varying  the  manner  of  getting  that  metal  into 
the  system,  by  changing  from  mouth  administration  to  inunction  through  the  skin. 
Treatment  does  not  cease  because  the  taking  of  mercury  is  given  up  for  a  period, 
since  excretion  goes  on  for  some  time  after  the  last  dose. 

It  must  not  be  forgotten  that  there  are  some  patients  who  exhibit  a  marked 
idiosyncrasy  to  mercury,  and  there  are  several  whom  it  makes  very  depressed. 
Depression  and  all  the  symptoms  which  constitute  what  we  call  mercurialism  are 
far  more  likely  to  follow  the  internal  administration  than  any  other  form,  and  this 
is  not  because  more  of  the  drug  circulates  in  the  system  when  it  is  prescribed  fer 
OS — on  the  contrary,  symptoms  of  mercurialism  may  become  manifest  long  before 
the  therapeutic  action  is  making  itself  felt.  I  have  no  doubt  in  my  own  mind,  that 
the  reason  why  we  see  so  much  chronic  superficial  glossitis  and  carcinoma  of  the 


356  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SYPHILIS. 

tongue  in  this  country,  is  largely  due  to  our  routine  treatment  of  syphilis  by  means 
of  pills.  In  countries  where  it  has  been  the  rule  for  many  years  to  treat  syjjhilis 
with  mercurial  inunctions  and  injections,  chronic  superficial  glossitis  is  a  very  rare 
condition.  "\Mien  I  first  became  attached  to  the  Lock  Hospital  and  took  over  the 
cases  of  my  predecessor,  who  had  always  used  pills,  I  was  obliged  to  examine  the 
mouths  of  nearly  every  patient.  Now  that  all  my  patients  are  treated  with 
injections,  it  is  very  seldom  that  a  mouth  has  to  be  examined,  and  patients,  while 
under  treatment,  are  almost  unknown  to  complain  of  sore  tongues,  sore  throats, 
&c.  Different  surgeons  have  different  views  on  the  matter,  and  some  still  maintain 
that  pill  treatment  is  the  best.  My  best  answer  to  this  is,  that  several  of  their 
patients  ask  if  they  can  come  upon  a  day  when  mercurial  injections  are  given,  as 
they  have  noticed  how  much  fitter  the  patients  look  who  are  having  them.  Out- 
patients in  a  large  hospital,  while  waiting  for  their  turn  to  be  examined,  have  ample 
opportunities  to  discuss  affairs  with  those  around  them,  and  as  the  average  patient's 
main  idea  in  attending  a  hospital  is  to  get  well  as  quickly  as  possible,  the  matter 
of  treatment  is  uppermost  in  their  minds ;  consequently  their  opinion  of  what  they 
consider  to  be  the  best  is  usually  the  correct  one. 

Because  of  the  great  disadvantages  of  the  oral  administration  of  mercury,  I 
always  use  mercurial  injections  or  mercurial  inunctions  when  the  patient  can 
afford  the  time  and  inconvenience  caused  by  the  latter.  For  reasons  already  stated, 
I  prefer  the  grey  oil  to  any  other  preparation.  If  the  patient  cannot  have  mercurial 
injections  because  he  is  travelling  or  something  of  that  sort,  then  he  must  take 
mercury  internally  or  in  the  form  of  suppositories. 

Iodine. 

The  most  potent  iodine  preparation  which  we  have,  is  undoubtedly  potassium 
iodide,  but  unfortunately  there  is  a  large  number  of  patients  who  cannot  take 
it,  partly  owing  to  its  depressing  action,  and  partly  because  of  its  readiness  to 
produce  iodism.  The  depressing  action  can  often  be  overcome  by  using  the 
ammonium  and  sodium  salts,  but  those  patients  who  readily  exhibit  the  symptoms 
of  iodism  will  usually  do  so  with  any  inorganic  salt.  Sometimes  the  symptoms 
of  iodism  can  be  prevented  by  the  administration  of  calcium  lactate  or  sodium 
bicarbonate.  Owing  to  the  frequency  of  iodism  with  the  inorganic  salts,  a  legion 
of  organic  compounds  have  been  put  upon  the  market,  all  of  which  are  stated  to 
be  equally  potent  as  the  inorganic  preparations  and  absolutely  innocuous. 

With  many,  iodism  does  not  supervene,  but  I  have  yet  to  find  one,  which  will 
be  entirely  innocuous,  when  given  to  a  patient  who  exhibits  a  marked  idiosyncrasy 
to  any  preparation  of  iodine,  and  such  patients  are  not  at  all  infrequently  to  be 


METHODS    OF   USING   ANTI-SYPHILITIC   DRUGS.  357 

met  with.     No  organic  preparation  appears  to  be  as  powerful  as  potassium  iodide. 
The  best  organic  preparations  are  iodoglidine,  sajodin,  and  tiodine. 

NUCLEINATE    OF    SoDA. 

There  is  no  doubt  that  nucleinate  of  soda  will  often  produce  a  period  of  quiescence 
in  a  case  of  degenerative  encephahtis,  when  every  other  kind  of  treatment  has 
proved  unavailing.  It  does  not  cure  the  disease,  but  a  patient  may  be  brought 
from  the  imbecile  state  into  the  normal  state,  and  may  remain  in  the  latter  for  some 
months.  This  drug  has  been  used  on  a  fairly  extensive  scale  by  Fischer  in  Prague, 
and  Donath  in  Budapest.  In  this  country,  Gordon  Lane  has  used  it  in  several  cases 
with  very  satisfactory  results.  As  the  drug  is  not  widely  known,  and  as  the  dose 
varies  with  different  observers,  I  will  mention  the  methods  of  the  three  men  whose 
names  I  have  above  referred  to. 

Fischer^  *  uses  0'5-3'0  grm.  dissolved  in  water  and  injected  intramuscularly 
every  three  to  five  days.  Donath^  ®  first  recommended  intramuscular  injections 
of  50-100  c.c.  of  a  2'5-3'0  per  cent,  aqueous  solution,  and  he  gave  eight  injections 
at  intervals  of  five  to  seven  days.  Donath^  now  employs  a  10  per  cent,  solution 
dissolved  in  normal  saHne  and  injects  from  10-50  c.c.  every  four  or  five  days  until 
six  to  twelve  injections  have  been  given. 

Gordon  Lane  tells  me  that  he  always  employs  a  2  per  cent,  solution  and  injects 
50-100  c.c.  once  a  week  for  about  eight  weeks. 

Some  hours  after  the  injection  the  patient  gets  a  rise  of  temperature  to  about 
104°  F.  The  next  day  it  falls,  to  rise  slightly  again,  and  as  a  rule  the  following 
day  it  falls  and  remains  normal  until  the  next  injection  is  given.  The  rises  of  tem- 
perature may  be  higher,  and  may  be  maintained  over  a  longer  period  than  this. 

The  injections  also  produce  a  hyper leucoc^'tosis. 

I  have  also  tried  nucleinate  of  soda  injections  in  cases  of  dementia  which 
have  resulted  from  s}'philitic  meningo-encephahtis,  and  with  considerable  improve- 
ment in  the  mental  condition,  in  spite  of  the  fact  that  the  syphihtic  process  had 
spontaneously  cured  itself.  It  is  highh'  probable  that  nucleinate  of  soda  would 
be  beneficial  in  other  syphilitic  nervous  manifestations,  but  as  to  whether  it  will, 
become  a  regular  adjunct  to  the  treatment  of  these  only  the  future  can  show. 

^  Homer  Swift  and  Ellis  (1914),  '•  Studies  from  Rockefeller  Inst,  for  Med.  Res.,"  xis,  471, 

492,  573. 
-  Ravaut  (1914),  '•  Aiinales  de  Medecine." 
3  Fischer  (1909),  "  Prager.  mediz.  Woch.,"  x.N:xiv,  401. 
^  IhkJ.  (1911),  "  Zeitschrf.  f.  d.  Ges.  Neur.  ii.  Psych.,"  iv  (orig.)  482. 
^  Donath  (1909),  ■'  Wicn.  klin.  Woch.,"  xxii,  1291. 
'•■  Ihid.  (1910),  "  Berl.  klin.  Woch.,"  xlvii,  1057. 


CHAPTER  XXXI. 
ULCUS  MOLLE   (SOFT   SORE). 

A  soft  sore,  or  Ulcus  molle,  is  a  specific  sore  caused  by  Ducrey's  bacillus.  The 
sore,  or  sores,  as  they  are  most  frequently  multiple,  occur  usually  on  the  genitals. 
They  may  occur  on  any  part  of  the  body,  as  they  are  easily  inoculable,  and  are 
also  autoinoculable.  I  have  seen  two  cases  of  a  .soft  sore  infection  on  the  finger, 
followed  by  suppuration  in  the  epitrochlear  gland.  The  usual  incubation  period 
is  about  three  days,  when  a  tiny  ulcer  appears,  and  spreads  rapidly.  The  sore 
is  a  true  ulcer,  the  base  of  which  is  uneven  and  covered  with  pus.  The  circumference 
of  the  ulcer  is  sharply  circumscribed,  but  irregular  in  outline,  because,  when  it 
spreads,  it  does  not  do  so  evenly;  often  one  part  of  an  ulcer  will  heal,  while  the 
other  end  extends.  The  edge  is  slightly  undermined.  The  ulcer  is  always 
surrounded  by  a  marked  inflammatory  ring,  the  inflammation  being  most  marked 
in  the  periphery  of  the  spreading  end.  The  ulcers  tend  to  heal  spontaneously,  but 
treatment  materially  hastens  the  process.  A  lymphangitis  is  often  to  be  observed, 
running  from  the  sore  along  the  penis  to  the  inguinal  lymphatic  glands,  on  both 
sides,  or  only  on  one  side,  and  not  necessarily  on  that  side  on  which  the  sore  is 
situated. 

One  of  the  most  interesting  points  about  the  soft  sore  infection  is  the  fact  that 
a  bubo,  i.e.,  suppuration  in  the  lymphatic  glands,  may  not  appear  for  weeks,  and 
even  for  months  after  the  sore  has  healed  and  has  been  forgotten. 

The  organism  which  causes  a  soft  sore  was  discovered  by  Ducreyi  -  ^,  and 
hence  is  often  called  Ducrey's  bacillus,  or,  because  of  its  shape,  the  streptobacillus. 

To  demonstrate  the  streptobacillus,  the  pus  from  the  edge  of  a  young  ulcer 
must  be  taken  ;  the  pus  from  an  old  ulcer,  or  from  a  bubo,  when  examined,  often 
gives  negative  results.  The  best  specimens  are  to  be  obtained  from  an  inoculation 
ulcer.  To  prove  that  a  bubo,  or  an  Ulcus  molle  serpiginosum,  is  due  to  Ducrey's 
streptobacillus,  it  is  sometimes  necessary  to  produce  an  inoculation  ulcer,  since  of 
all  the  known  venereal  infections  which  cause  ulcers,  the  soft  sore  infection  is  the 
only  one  which  is  autoinoculable.     If  the  observer  wishes  to  produce  an  inoculation 


Plate  34. — A  SmaLE  Soft  Sore. 

The  sore  is  sharply  circumscribed,  the  edge  is  raised  and  undermined, 
the  base  is  covered  with  pus,  the  sore  is  surrounded  Yiy  acute  inflanunation, 
which  has  produced  a  Paraphimosis  interna  and  acute  inflammatory  oedema 
of  the  prepuce. 


Plate  34. 


Facing  v.  SS8. 


caii'^c  ■  ;!nf!.     Th< 


U  :    ■';'■■'. 

,ii<.i)/;ii(iinillni  oJu'iB  \A  bsbfu/onua.ai  t^t>»  "(jll  ,<sx/q  xitiw  b-o9»oo  ei -jBfid'sri.t 
no^finirneftfii  sIbob  fenjs  i^'jjni  aWomVAtiiMB'^  s  bsniiboxq  aed  1(011(7/ 

.u;)iiq9iq  -irlt  I11 


^JH  !i  i'ltn'sH 


Plate  34. 


1. 

A  low  power  (  x  15)  raicroscopic  section  of  tlie  sore  ou  plato  34.  On  lioth  siiles  of  the 
drawing,  cjiitlielinni  is  to  be  noticed.  Tlie  nearer  to  tlie  sore  the  tliinner  the  epitlieliuiii 
becomes.  The  epithi-linm  further  away  from  the  sore,  except  for  a  slii^^ht  hypertrophy  of 
the  papillae,  is  scarcely  altered.  The  orjranisms  to  bo  found  in  this  type  of  soft  sore  occur  ou 
the  surface  iu  the  area  ringed,  and  the  figure  below  is  a  drawing  from  tlie  centre  of  this  area. 


This  is  a  higher  power  (  x  270)  microscopic  picture  of  the  sore  depicted  on  plate  ;U. 
Except  for  a  slight  connective-tissue  celled  hyperplasia  the  main  changes  are  those  which 
affect  the  leucocytes.  Iu  a  sore  of  this  type  there  are  few  or  no  plasma  cells,  the  lymphocytes 
ai'e  increased,  but  the  cell  which  is  in  greatest  abundance  is  the  polymoii>honnclear  leucocyte. 
In  this  fypt'  of  soft  sore,  which  is  the  most  common,  the  tissue  is  strongly  oxyphilic.  I.e.  it 
exhibits  a  marked  ailinity  for  tlie  methyl  green  dj^e,  when  staiued  sifter  rajijienln'ini's  nii'ilmd. 
The  niuri-  oxyphilic  tissue  is.  and  the  fewer  the  plasma  cells,  and  the  largi-r  the  nuniln-r  (-f 
lyniphucytes  ami  polymoi-phouuclear  leucocytes,  it  contains,  the  greater  tlie  power  tlu^  liost 
has  over  the  disease,  henfce  the  more  beuigu  the  infection,  and  the  greater  the  mpiditj-  with 
whii'h  it  will  vanish. 

Plate  35. 


Follou-8  rititc  34. 


Plate  3fi. 

This  is  a  liigher  power  (x  1,500)  still  of  the  second  figure  on  Plate  35, 
to  show  the  type  of  organism,  that  is  to  be  met  with  in  the  most  common 
form  of  soft  sore.  It  will  be  noticed  that  the  bacilli  are  arranged  in  groups, 
and  that  each  growp  is.  made  up  of  chains,  which  vary  somewhat  in  length. 


\^ 


Follows  Plait  35. 


,g£  aJfill  no  siugci  hnoaoe  eiii  io  liiis  (006,1  x  )  i9v/oq  i9il§iif  £  ai  kWT 
no/tirnoo  Jgoin  adi  iii  diivi  Jem  sd  o*  ei  iadi  .roairifi^io  io  aq'{i  arfl  woria  oj 
,8qooi§  iii  bsgnfiTi*  9i6  iUioeJ  ari*  icHi  baoiJoii  ad  lliw  .tl     .9io8  ilos  io  irrio} 
.riisi"'5f  ni  Jeriwsniop.  '^by  doiri'w  .snifirif)  io  qu  ebeai  ei  qi/oii!  riofia  iadi  has 


.as  •toSS  nioU«^ 


Plate  30. 


ULCUS    MOLLE    (SOFT    SORE).  359 

ulcer,  the  abdomen  fshould  always  be  chosen,  since  the  skin  of  the  arms  or  legs  may 
fail  to  react. 

The  streptobacillus  stains  well  with  most  dyes,  especially  with  carbolfnchsin, 
polychromemethylene  blue,  and  pj-ronin,  in  Unna's  carbolpyronin-methyl  green 
mixture,  but  it  is  Gram  negative. 

The  streptobacillus  is  an  extracellular  organism,  but  sometimes  it  is  found 
intracellularly  situated,  when  it  becomes  polymorphic.  The  full  significance  of 
the  intracellular  habitat  will  be  shown  later. 

Even  the  extracellular  forms  are  not  always  exactly  alike,  so  it  would  be  as 
well  to  enumerate  them  all,  and  I  cannot  do  better  than  adopt  Tomasczewski's* 
admirable  classification. 

1.  Very  short  rods,  which  are  difficult  to  distinguish  from  cocci,  0'4  /^  long 
and  0-3  to  0-35  /u  wide. 

2.  Short,  thick  rods,  with  rounded  ends,  1'5  to  1  '7  jii  in  length,  and  0'4  fi  in 
breadth.     Bacilli  of  this  form  are  usually  found  isolated. 

3.  Dumb-bell  forms.     These  are  usually  found  in  groups. 

4.  Forms  like  diplococci,  first  described  by  Unna*  as  the  "  Doppelpunkt  bacillus," 
and  bv  Ducreyi  as  the  "Achterform."  Length,  I'O  to  1'5  /x;  breadth,  0'3  to 
0-4  ft. 

5.  The  "en  navette"  form  of  the  French®  '  or  the  "Schifichenformen"  of  the 
Germans.  These  are  rods  which  have  an  unstained  point  in  the  centre.  Length, 
I'l  to  1'5  (U  ;   breadth,  0"5  to  0"6  /j. 

In  films,  the  streptobacillus,  as  its  name  denotes,  is  frequently  found  in  long 
chains,  and  this  is  characteristic  of  the  specimens  made  from  cultures. 

The  streptobacillus  can  be  demonstrated  easily  in  sections,  and  it  is  always 
to  be  found  in  the  neighbourhood  of  the  undermined  edge.  This  undermined  edge 
alone  usually  suffices  to  allow  one  to  make  a  good  guess  of  the  nature  of  a  section 
shown  for  diagnosis.  Barring  this  point,  and,  of  course,  finding  the  causative 
organism,  a  section  of  a  soft  sore  is  indistinguishable  from  that  of  any  other  granu- 
lomatous ulcer.  In  my  opinion,  the  best  method  of  showing  up  the  bacilli  in  a 
section  is  to  stain  it  with  pyronin  and  methyl  green  (Plate  36). 

Culturing  the  organism  is  not  an  easy  matter,  partly  owing  to  the  fact  that  other 
organisms  flourish  readily  on  soft  sores  ;  therefore,  if  a  pure  culture  is  desired,  it 
is  best  to  produce  an  inoculation  sore  ;  and  partly  because  a  special  medium  is 
required. 

WTienever  one  wishes  to  make  a  culture  of  the  causative  organism  of  a  lesion 
it  may  usually  be  taken  for  granted  that  the  organism  in  question  is  more  resistant 
to  antiseptics  than  those  which  affect  the  lesion  secondarily. 


360 


THE   BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SOFT   SORE. 


The  streptobacillus  is  no  exception  to  this  rule  ;  hence,  if  there  are  reasons 
why  an  inoculation  sore  should  not  be  made,  a  young  sore  can  be  well  bathed  with 
any  mild  antiseptic  lotion,  before  the  culture  tubes  are  inoculated.  Blood  agar  is  the 
best  mediimi  on  which  to  grow  the  streptobacillus.  The  blood  must  be  fresh, 
and  must  be  mixed  in  equal  quantities  with  agar.  Guinea-pig's,  rabbit's,  or  human 
blood  can  be  used.  The  medium  must  be  moist,  and  it  is  necessary  to  have  a  fair 
quantity  of  condensation  fluid  at  the  bottom  of  the  tube. 

If  the  inoculation  has  succeeded — and  in  about  eight  attempts  out  of  ten  it 
does  not — a  growth  begins  to  appear  in  about  48  hours  in  the  neighbourhood  of 
the  condensation  fluid,  in  small,  round,  shiny  colonies,  which  increase  rapidly  in 
size,  and  on  about  the  third  or  fourth  day  they  exhibit  a  grey-white  to  a  grey-yellow 
tint.  The  colonies  are  firmly  adherent  to  the  medium,  and  can  only  be  removed 
in  toto.  Once  a  pure  colony  has  been  obtained,  it  is  a  simple  matter  to  inoculate 
other  tubes  with  it,  but  these  must  be  inoculated  not  later  than  the  fourth  day, 
as  the  streptobacillus  in  culture  dies  very  quickly.  The  streptobacillus  remains 
alive  longer  when  kept  at  room  temperature,  than  when  kept  in  an  incubator.  The 
streptobacillus  is  very  susceptible  to  rises  in  temperature,  and  this  fact  has  largely 
been  made  use  of  in  treating  Ulcus  molle.  Treating  the  sores  with  hot-air  baths 
is  a  favourite  procedure  with  many  clinicians. 

Films  made  from  a  colony  show  the  bacilli  in  chains.  Individually,  the  bacilli 
vary  in  length  from  1'5  to  2'5  ju,  and  in  breadth  from  O'-i  to  0*5  //.  The  coccal- 
like  form  is  also  to  be  seen,  but  only  in  old  cultures  are  the  dimib-bell  and  "'  doppel- 
punkt  "  foi'ms  to  be  met. 

In  the  condensation  fluid,  the  organism  flourishes  better  than  on  the  solid 
medium,  the  chains  are  longer,  but  the  morphology  of  the  bacillus  is  the  same. 

In  some  specimens  the  bacilli  seem  to  have  capsules. 

The  streptobacillus  is  non-motile,  and  it  is  only  pathogenic  for  man  and  for 
the  higher  and  lower  apes. 

Vhus  molle,  although  a  widespread  disease,  favours  some  countries  more  than 
others.  I  have  noticed  over  and  over  again  how  much  more  common  it  is  on  the 
Continent  than  in  England,  and,  oddly  enough,  it  appears  to  be  more  common  in 
London  at  some  times  than  at  others.  Whether  there  is  a  seasonal  variation  or  not, 
I  have  been  unable,  as  yet,  to  determine.  In  my  experience,  Ulcus  molle  is  more 
frequently  to  be  met  with  in  men  than  in  women. 

Ulcus  molle  afiects  difierent  individuals  in  various  ways.  In  some,  the  sores 
heal  spontaneously  in  a  few  days  ;  in  others,  especially  those  who  have  tight 
foreskins  and  have  to  take  much  exercise,  the  ulcers  spread  rapidly,  and  they  may 
even  become  phagedaeuic. 


The  patient  has  two  sores,  one  on  the  penis  and  one  on  the  scrotum.  The 
penDe  sore  is  sharply  circumscribed,  irregular  in  outline,  an  ulcer,  which  is 
slightly  depressed  beneath  the  surface,  but  the  edge  is  not  undermined 
and  there  is  no  circumferential  inflammation.  The  scrotal  sore  is  sharply 
circumscribed,  more  regular  in  outline,  an  ulcer,  which  is  well  raised  above 
the  surrounding  and  healthy  skin.  The  edge  is  red  and  inflamed,  but  there 
is  no  area  of  acute  inflammation  exterior  to  it.  It  \vill  be  noticed  that  both 
sores  are  red,  and  that  they  are  not  covered  with  pus.  The  sores  were  rou^li 
on  the  surface  and  bled  easily  on  friction.  The  sore  on  the  scrotmu  is  a 
beautiful  example  of  the  so-called  Ulcus  molle  devatum.  The  incubation 
period  of  this  type  of  sore  is  often  a  long  one,  it  may  be  a  matter  of  weeks, 
and  it  may  be  extremely  resistant  to  treatment.  It  was  the  boat-shaped 
form  of  the  streptobaciUus  which  caused  the  sores  in  this  case.  The  boat- 
shaped  form  of  the  bacillus  is  never  found  in  such  great  numbers  as  the 
ordinary  streptobaciUus,  nor  does  it  occur  in  groups  of  long  chains.  The 
bacilli  are  fewer  in  number  and  more  irregularly  scattered  about. 


Facing  p.  360. 


tin:  iiif 
.Vfi  a*.jq 

edX  .omJoioa  edJ  xio  atio  biiu  i-.ln-xi  '^'"  '"^  '"'o  <8oio8  out  gad  JiioilBq  oil'l' 
ei'iioiiiW  .iooli;  ttk'.on'diuo  hi  liilugatii  .bsrfitasamotio  T{fqT48if3  ai  alda  ann«r' 
bomnnsbnurlon'ai  sgfae  pdi  iud  ..soahiia '  adt .  djfaspnod  b^eapaqai)  vjidsii^',  :, 
XlqriJiiiii  81  810^  1.^1013^. 9flT  .iioil^;fuii.p[ixii  l£iin9T9)xau3tia  on-ci  sisxil  biii; 
svocIb  bwim  Hoy/  ai  ^^''l""  .laalu  fifi  ^snittoo  ai  jfifi/ggT  aiora  .badhoexnumi ) 
oTjrit  tijil  .[j'tmeHni  ban  bei  111  ogba  oriT  .tiijla  nrf3lfl«f  ()fic  gnibnuoTiiia  sriJ 
tlJod  iadi  b'ljiio/i  9cf  llr«  Jl  .Ji  ot-ioiTjJxg  iioijBuixafihrii  !>}ijob  to  Bfcic  oa  ^i 
rigijoi  oi9'«  «8ioa  9dT  .a«q  rfliv/' fc(M6'?b3.jQi<,a(^«;itf)riJ  lisrfj  bnfi4><>^  9i«  aoiu' 
B  ai  uiuioiaa  adJ  no  Ttoii  pd|T  .aoilohi  no  .uliaea,  Iwld  fauc  MshiiB  adJ  no 
noiJBiiuofii  ydT  ,i«»sSn«3h  alSom  mjoJ'J  bollBo-oa  adi  lo  slqrufizo  luliiuised 
,«j(39v/  to  ioUboi  *  dcf'^Bm  ii  ,9nb  §noI  js  riaito  ?ir  oiop  to  tiq-f*  eirfi  to  boiigqi 
beqiB/le-lBod  ■  oril  ac'w  ^I  .hiauiJaaiJ  oi  IneJKwai  •^IsnoiJ/.s  ad  xsta  ii  bna 
-ieod  srfT  J9»fi?  aiito  nt  aa-ioa  ad*  boatiaa  il»id^.  eutUo«fto>q?!K|avs4*;i<?  if '93^)1  ii 
arfl  sifi  8i9(lftiuft  Jfia'ig  dgoa  rii  bnnol  -w/an  si  auUiofld  od4  to  onol  bsqads 
odT  .Rnicriv  gnol  to  Bqnoig  rii  juuoo  Ji  eaob  ion  .auUiojscIoiqaida  '^TBiiiLio 
.)i/ocIb  b9i9W*t)e  "^hsfagswi  aiom  ibitinadraun  ni  lawal  aie  iifioed 


.08£  .<\  ^ni^o* 


Plate  37 


,^' 


>,K«»-**»'^^*f'^**H,^ 


.V^ 


V 


1. 

Tliis  is  a  luw  powur  (  x  12)  microscopic  section  of  tlie  scrotal  sore  ilcpictort  ou  plate  37.  The  elevated 
cliaracter  of  the  ulcerate'l  area  is  -well  sho-i™,  and  the  riiip  represents  tlie  site  where  the  bacilli  were 
found.  Contrasted  with  plate  oo  (1)  it  will  be  noticed  that  the  epitlii-linni  nearest  to  the  nicer  is  markedly 
hypertrophied,  that  in  the  corium  there  is  a  prononncerl  coum-ctive  tissne  hyperplasia  and  some 
afteratiou  in  the  walls  of  the  blood  vessels. 


Tliis  is  a  higher  power  (x  270;)  microscopic  section  of  the  scrotal  sore  depicted  on  plate  37.  The 
epithelinm  is  acanthotic,  as  it  nsuallv  is  in  chronic  infections.  There  is  a  marked  connective  tissue  and 
endothelial-celled  hvperplasia,  anil" instead  of  a  preponderance  of  polymorphonuclear  leucocytes,  the 
cellular  infiltration  consists  of  mainly  plasma  cells  and  lymphocytes.  The  tissue  in  this  type  of  sore,  or 
indeed  of  any  chronic  sore,  is  i:)yrouiuophile. 


Plate  38. 


Folhirs   Plate  37. 


ULCUS   MOLLE    (SOFT   SORE).  361 

Exercise  is  more  likely  to  set  up  or  to  increase  any  tendency  there  may  be 
to  lymphangitis  and  suppurative  adenitis.  A  sore,  after  it  has  persisted  for  some 
time,  may  develop  what  may  be  called  a  pseudo-induration,  and  hence  suggests 
to  the  unwary  a  primary  sore.  Such  a  difficulty  in  diagnosis  need  never  arise,  if 
the  observer  will  always  remember  that,  however  long  a  soft  sore  persists,  and 
however  wide  its  dimensions  become,  it  never  loses  its  clinical  characters — the  under- 
mined edge,  with  its  surrounding  area  of  inflammation,  is  practically  always 
present. 

Every  student  is  taught,  and  rightly  so,  too,  that  a  soft  sore  may  develop  into 
a  chancre,  and  that  the  change  may  be  detected  by  the  induration  which  supervenes. 
A  soft  sore  may  become  a  chancre,  but  not  nearly  so  often  as  one  is  led  to  believe. 
A  soft  sore  may  become  indurated,  and  yet  not  become  a  chancre.  If  a  chancre 
is  going  to  develop  upon  a  soft  sore,  the  change  that  takes  place  is  the  disappearance 
of  the  undermined  edge,  and  a  levelhng  up  of  the  base  of  the  ulcer. 

When  a  soft  sore  is  situated  on  the  froenum,  haemorrhage  from  the  froenal 
artery,  owing  to  the  spread  of  the  ulceration,  is  a  complication  which  should  always 
be  borne  in  mind.  The  haemorrhage  has  never  been,  in  my  experience,  severe, 
but  it  is  usually  quite  severe  enough  to  alarm  the  patient. 

Although  the  main  characteristics  of  a  soft  sore  are,  practically  always  the 
same,  there  are  some  different  clinical  forms  to  be  met  with,  which  require  very 
careful  mention,  owing  to  the  difficulty  they  cause  in  differential  diagnosis. 

Ulcus  Molle  Elevatum. 

This  sore  differs  from  the  ordinary  soft  sore  in  being  raised  above  the 
surface  (Plate  37).  It  is,  nevertheless,  an  ulcer,  but  the  edge  is  not  undermined. 
This  type  is  often  single,  the  surrounding  inflammation  is  not  so  marked 
as  it  is  in  the  ordinary  sore,  and  it  is  extremely  resistant  to  treatment.  Pseudo- 
induration  is  liable  to  be  met  with  in  this  type  of  sore  ;  hence  it  is  very  apt  to  be 
mistaken  for  a  chancre.  Another  peculiarity  that  this  type  of  sore  presents,  is  its 
not  infrequent  long  incubation  period. 

Ulcus  Molle  Miliaee. 

According  to  Tomasczewski,*  this  type  is  more  commonly  to  be  met  with  in 
women  than  in  men,  and  the  sites  of  predilection  in  the  former  are  the  labia 
majora  and  the  perineum.  Each  lesion  is  a  raised  papule,  in  the  centre  of 
which  there  is  a  crateriform  ulcer,  and  it  looks  at  first  sight  like  a  hair  follicle 
infection.  The  lesions  persist  for  some  time,  and  there  is  usually  a  very  great 
number  of  them.  I 


362  the  biology,  clinical  aspect  and  treatment  of  soft  sore. 

Ulcus  Molle  Phagedaenicum. 

A  soft  sore,  as  a  rule,  does  not  become  phagedaenic  unless  it  is  hidden 
beneath  a  tight  foreskin,  and  the  first  appearance  of  the  phagedaena  is  a 
perforation  of  the  foreskin.  In  very  severe  cases  part  of,  or  the  whole  penis, 
may  be  destroyed.  Phagedaena  is  a  not  common  complication  of  a  soft  sore  ; 
it  is  certainly  more  often  met  with  in  syphilis,  and  I  cannot  help  thinking 
that  the  free  use  of  carbolic  acid — a  drug  to  which  many  individuals  show  a 
marked  idiosyncrasy — has  often  been  responsible  for  the  complication.  As  is 
the  case  in  syphilis,  the  specific  organism  is  destroyed  when  a  sore  becomes 
phagedaenic.  In  nearly  all  phagedaenic  sores,  the  fusiform  bacilli  and  the  spiro- 
chaetae  which  exist  in  symbiosis  with  them,  organisms  which  appear  to  be  the 
cause  of  Vincent's  angina  and  Balanitis  gangrenosa,  are  usually  to  be  found. 
Indeed,  they  are  really  the  cause  of  the  phagedaena. 

Ulcus  Molle  Seepiginosum. 

I  am  here  pubhshing  a  recent  article  of  mine,  which  appeared  in  the  "  British 
Journal  of  Dermatology,"^  because  the  condition  is  much  more  common  than  is 
thought  to  be  the  case,  and  it  is  almost  invariably  wrongly  diagnosed,  and  unless 
exactly  the  right  treatment  is  given,  curative  measures  are  of  no  avail. 

The  primary  lesion  is  a  furuncle,  the  edges  of  which  become  blue,  bluish-white, 
and  then  break  down  until  a  distinct  ulcer  is  formed. 

The  base  of  the  ulcer  is  fleshy,  uneven,  and  secretes  freely.  The  edges  are 
ragged,  look  as  if  they  had  been  gnawed,  and  are  deeply  undermined  ;  the  over- 
hanging portion  is  cedematous  and  bluish- white  in  colour  ;  external  to  this  the  colour 
becomes  purplish,  and  still  further  out,  and  spreading  for  some  distance  into  the 
healthy  tissue,  one  sees  the  red  colour  of  inflammation.  The  inflammatory  zone 
is  most  marked  where  the  ulcer  is  spreading,  as  it  invariably  spreads  in  one  part 
more  than  in  another  ;  in  fact,  one  pole  may  heal  while  the  other  is  steadily 
advancing.  A  very  favourite  route  for  one  tongue  of  the  ulcer  to  take  is  down 
the  genito-crural  fold.  Occasionally  such  a  process  reaches  as  far  back  as  the 
anus. 

Case  52. — A  man,  aged  25  years,  was  shown  by  Mr.  Shillitoe  before  the 
Dermatological  Section  of  the  Royal  Society  of  Medicine,  June  15th,  1911 
(Plates  39  and  40  are  from  this  case),  as  a  case  of  (?)  Granuloma  inguinale.  The 
patient  consulted  Mr.  Shillitoe  first  on  March  16th,  1911,  and  gave  the  following 
history  : — "  Just  before  last  Christmas  he  developed  multiple  sores  around  the 
corona  (soft  sores),  and  a  bubo,  which  was  opened  on  January  10th,  and  which  had 


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ULCUS   MOLLE    (SOFT   SOKE).  363 

not  healed  ou  his  arrival  in  England.  He  left  Singapore  on  February  17th,  having 
already  developed  the  three  ulcers  still  present  in  his  left  groin.  He  was  told  he 
had  syphilis,  and  was  advised  to  have  salvarsan.  During  the  voyage  home,  he  took 
150  tablets  of  3  minims  each  of  iodine,  together  with  local  applications  of  pure 
carbolic,  silver  nitrate,  &c.,  without  any  marked  effect  on  the  ulcerations.  He 
had  been  four  years  in  the  East,  and  had  been  really  ill  with  malaria  during  the 
first  year  only.  Ten  years  ago  he  had  albuminuria,  following  typhoid  fever.  The 
urine  had  been  periodically  examined  since,  without  any  fresh  appearance  of 
albumin,  until  early  in  February. 

"  When  Mr.  Shillitoe  saw  hun  on  March  16th,  the  urine  was  acid,  sp.  gr.  1024, 
and  contained  a  decided  amount  of  albumin.  He  had  three  superficial  ulcerations 
in  the  left  groin  and  an  unhealed  bubo.  The  bases  of  the  ulcerations,  which  were 
not  punched  out,  were  glazed,  devoid  of  granulations,  and  discharged  a  thin 
sanious  fluid  ;  the  edges  were  rounded  and  firm.  Mr.  Shillitoe  did  not  consider 
them  to  be  specific,  nor  could  he  find  other  evidence  of  syphilis. 

"  March  23rd  :  Wassermann  reaction  positive  ;  no  albumin,  so  he  was  put 
under  mercury. 

"  March  31st :  The  sores  not  healing,  Mr.  Shillitoe  gave  him  in  addition 
sanatogen  internally  and  externally. 

"  April  12th  :  The  sores  were  gradually  closing  and  granulations  were  appearing, 
which  bled  readily.  He  has  increased  one  pound  in  weight,  now  10  st.  12  lb.  ; 
there  was  a  small  trace  of  albumin  and  Herpes  pj'eputiaUs. 

"  April  21st  and  again  on  24th  :  0 '  59  grm.  of  salvarsan  were  given  intravenously. 
"  April  27th  :    The  .sores  were  sjjreading  at  the  edges." 

The  painting  was  done  in  June,  after  the  excision  of  one  ulcer  had  been 
attempted,  without  success.  Later  X-rays  and  also  radium  were  tried,  with  no 
better  results.  Every  conceivable  drug  was  tried  locally,  but  the  extension  could 
not  be  stopped.  The  only  drug  which  seemed  to  do  the  least  good  was  potassium 
iodide  given  internally.  "When  the  salt  was  pushed  up  to  200  grains  per  diem,  and 
the  sores  washed  with  perhydrol,  and  then  dusted  with  iodoform,  the  ulcers,  after 
several  weeks,  completely  healed. 

A\Tien  the  ulcers  began  to  heal,  zinc  ionisation  was  tried  with  a  little  success  ; 
iodine  and  copper  ionisation  were  useless. 

The  Wassermann  reaction  was  positive,  because  the  patient  had  had  a  very 
bad  attack  of  malaria  three  weeks  prior  to  the  test  being  made. 

Owing  to  the  fact  that  the  ulcers  did  not  heal,  the  question  of  tubercle  was 
raised,  but  when  there  was  no  reaction  to  tuberculin,  and  both  von  Pirquet's  and 
Moro's  reactions  were  negative,  that  disease  was  excluded. 


364  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   SOFT    SORE. 

Several  films  and  cultures  were  made,  with  negative  results  ;  these  were  again 
repeated  when  the  ulcers  secreted  more  freely,  and  every  time  a  pure  culture  of 
proteus  resulted. 

Vaccines  made  therefrom  stopped  the  discharge,  and  removed  the  fearful 
odour  to  which  it  gave  rise,  without  in  any  way  causing  the  ulcers  to  heal.  The 
proteus  was  Proteus  vulgaris  ;  it  was  Gram  negative,  very  motile,  and  the  bacilli 
varied  in  length.  It  gave  acid  and  gas  in  glucose  and  lactose,  and  it  clotted 
peptonised  milk.  It  rapidly  liquefied  gelatin.  A  rabbit  which  was  injected  died  in 
forty-eight  hours  from  acute  septicaemia. 

Pieces  of  tissue  were  removed  and  injected  into  a  rabbit,  a  guinea-pig,  and  a 
mouse,  intravenously,  intraperitoneally,  and  subcutaneously  respectively.  Only 
the  mouse  died  a  fortnight  later,  and  in  spite  of  a  thorough  examination  of  all  its 
organs  nothing  abnormal  was  discovered. 

The  bloods  of  the  rabbit  and  guinea-pig  were  tested  from  time  to  time,  with 
negative  results. 

The  patient's  own  blood-count  was  as  follows : — Red  blood-corpuscles,  4, -500, 000  ; 
white  blood-corpuscles,  12,500;  polymorphonuclear  leucocytes,  51 '56  per  cent.; 
lymphocytes,  46 '35  per  cent.  ;  eosinophiles,  1'99  per  cent.  ;  basophiles,  0'207  per 
cent.  ;    lymphocytes — large,  26  "7  per  cent.,  small,  73  "3  per  cent. 

The  lymphocytosis  was  doubtless  due  to  the  foregone  attack  of  malaria,  and 
had  nothing  to  do  with  the  complaint. 

Just  on  the  chance  that  a  fungus  might  be  the  cause  of  the  mischief,  I  tried 
some  agglutination  tests  with  a  spore  emulsion  of  sporotrichosis,  with  negative 
results . 

Two  pieces  were  removed  and  examined  histologically  (Plate  40). 

The  picture  was  typical  of  a  granuloma.  There  were  no  giant  cells,  but  a 
large  number  of  aminoplasma  cells.  In  places,  the  walls  of  the  vessels  were  very 
much  thickened,  so  that  every  pathologist  who  saw  the  sections  diagnosed  syphilis 
or  tubercle  at  once. 

In  the  most  superficial  layer  of  the  undermined  portion,  streptobacUli  were 
to  be  found.  The  baciUi  were  Gram  negative,  usually  in  pairs,  and  never  in  chains 
or  more  than  five  or  six.     No  intracellular  organisms  were  to  be  found. 

Having  demonstrated  Ducrey's  bacillus  in  section,  I  made  several  attempts 
to  culture  the  organism  on  both  rabbit's  and  human  blood-agar,  but  failed. 

Case  53. — A  man,  aged  27  years,  who  had  spent  several  years  in  the  Malay 
States,  came  home  to  consult  me  for  some  chronic  ulcers  of  the  groin.  In  both 
groins  were  several  ulcers,  indistinguishable  from  those  seen  in  the  coloured 
illustration  ;    they  were  extending  above  on  to  the  abdomen,  And  below  on  to  the 


ULCUS   MOLLE    (SOFT   SORE).  365 

thighs,  and  on  both  sides  they  had  reached  far  down  in  the  genito-crural  folds. 
The  ulceration  began  seven  months  before  I  saw  the  patient. 

Five  years  before  he  had  had  some  sores  on  the  penis  {Ulcera  mollia),  which 
healed  up  without  any  complications  arising  therefrom,  such  as  bubo,  etc.  In 
November,  1911,  the  patient  fell  over  a  log  of  wood,  with  the  result  that,  two  days 
later,  a  swelling  appeared  in  the  skin  in  the  iuguino-scrotal  folds  on  both  sides.  The 
swellings  behaved  like  boils,  so  were  lanced,  and  from  that  time  onwards  they 
became  ulcers,  which  rapidly  tended  to  increase  in  size.  As  no  local  application 
was  of  any  use,  the  patient  was  put  under  an  anaesthetic,  and  the  ulcers  were  well 
scraped,  with  the  result  that  they  spread  more  quickly  than  ever. 

When  I  first  saw  the  patient,  he  could  not  walk  owing  to  the  pain  caused  by 
the  ulcers  ;  the  ulcers  discharged  freely,  and  had  that  peculiar  indescribable  odour 
which  I  have  noticed  in  every  case  I  have  seen. 

I  made  some  films  from  some  secretions  from  under  the  overhangizig  portion 
of  skin  in  the  region  whore  an  ulcer  was  spreading,  and  succeeded  in  obtaining 
Ducrey's  bacillus.  Separate  streptobacilli  were  to  be  seen,  also  many  in  pairs, 
and  some  in  chains,  but,  contrary  to  what  one  finds  in  ordinary  soft  sores,  many  of 
the  leucocytes  were  crammed  with  a  different  form  of  Ducrey's  bacillus,  which 
will  be  described  later.  To  prove  that  the  ulcers  were  due  to  Ducrey's  bacillus, 
I  inoculated  the  patient's  arm.,  and  succeeded  in  obtaining,  after  the  usual  incubation 
period,  a  typical  soft  sore,  from  which  I  was  able  to  isolate  the  same  bacillus. 

Treatment  consisted  in  gradually  increasing  doses  of  iodides,  until  the  patient 
took  200  gr.  2)er  diem  ;  the  maximum  was  maintained  for  one  week,  and  then 
gradually  decreased,  and  so  on  until  the  ulcers  had  completely  healed,  which  took 
place  in  three  and  a  half  months. 

Locally  the  ulcers  were  painted  with  camphphenol,  and  then  dusted  with 
iodoform. 

Case  54. — A  man,  aged  32  years,  who  had  spent  the  last  few  years  in  Ceylon, 
consulted  me  for  an  ulceration  he  had  in  his  groin  and  upper  part  of  the  thigh. 
The  ulceration  started  in  the  groin  as  a  little  furuncle,  three  years  after  he  had  had 
some  sores  on  his  penis  {Ulcera  mollia).  He  had  never  had  a  bubo.  The  furuncle 
became  an  ulcer  which  spread  down  over  the  thigh,  so  that,  when  I  saw  the  patient, 
practically  the  whole  anterior  surface  of  the  upper  half  was  one  huge  ulcer,  although 
the  superior  part  had  commenced  to  heal.  The  ulcer  had  persisted  for  two  and 
a-half  years,  and  in  spite  of  having  had  every  kind  of  treatment  imaginable,  no  good 
had  resulted.  From  this  ulcer  I  also  found  the  intracellular  form  of  Ducrey's 
bacillus.  The  treatment  consisted  in  iodides  internally,  camphphenol  and  iodoform 
externally,  and,  in  addition,  the  patient  had  five  intravenous  injections  of  tartar 


366  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SOFT   SORE. 

emetic  every  four  days,  O'l  grni.  in  100  c.c.  saline,  with  the  result  that,  in  three 
weeks,  the  ulcer  completely  healed. 

Case  55. — A  man,  aged  36  years,  a  native  of  India,  had  an  ulceration  of  both 
thighs  almost  down  to  the  knees,  and  above  the  groin  practically  the  whole  of  the 
lower  third  of  the  abdomen  was  involved.  The  ulceration  had  persisted  for  over 
five  years,  and  had  not  responded  to  any  treatment  that  had  been  given. 
Unfortunately  this  patient  died  before  anything  could  be  done. 

Case  56. — A  man,  aged  34  years,  who  had  spent  some  years  in  the  tropical 
part  of  Australia,  consulted  me  for  a  chronic  ulceration  of  one  groin.  The  patient 
had  had  a  soft  sore  and  a  bubo  resulting  therefrom,  which  latter  had  to  be  incised. 
The  soft  sore  healed  rapidly,  but  the  edges  of  the  bubo  became  ulcerated,  until  a 
typical  picture  of  Ulcus  molle  serpiginosum  presented  itself.  This  ulcer  rapidly 
healed  under  potassium  iodide  internally,  camphphenol  and  iodoform  externally, 
and  tartar  emetic  intravenously. 

Sunmiing  up  these  cases,  we  find  that  we  are  dealing  with  a  peculiarly  chronic 
form  of  ulceration,  which,  at  irregular  periods,  invariably  follows  a  soft  sore 
appearing  independently  of  a  bubo,  or  after  a  bubo  has  been  incised.  It  is  further 
characterised  by  the  fact,  that  in  every  case  the  patient  had  lived  in  the  tropics. 

It  is  quite  clear  that  any  operative  procedure  makes  matters  very  much  worse, 
and  that,  unless  exactly  the  specific  treatment  is  prescribed,  nothing  is  of  any  avail. 

The  best  treatment  appears  to  be  to  give  potassium  iodide  internally,  to  apply 
camphphenol  and  iodoform  externally,  and  healing  can  be  hastened  by  giving 
injections  of  tartar  emetic  intravenously  and  subjecting  the  ulcers  to  zinc  ionisation. 
AVhether  the  antimony  acts  specifically  or  not,  I  am  not  prepared  to  say,  as  the 
possibility  arises  that  its  action  is  due  to  freeing  the  iodine,  which  has  undoubtedly 
a  specific  action.  The  reason  I  suggest  this  is,  that  after  every  injection  of  antimony, 
the  patients  always  had  a  violent  fit  of  coughing,  which  lasted  for  about  twenty 
minutes — a  cough  resembling  that  that  might  be  produced  by  inhaling  iodine. 

Nearly  all  the  cases  of  Ulcus  molle  serpigitwsmn  have  followed  an  operation 
on  a  bubo. 

Bacteriology. — In  describing  Ducrey's  bacillus,  one  must  bear  in  mind  the 
extraordinary  morphological  differences  which  the  organism  may  present. 

The  "  en  navette  "  type  is  rare  in  soft  sores,  but  extremely  common  in  Ulcus 
molle  serpiginosum  ;  the  short  rods  and  diplococcal  forms  were  also  found,  but 
they  were  always  extracellular,  while  the  "  en  navette  "  form,  although  found  extra- 
cellularly,  was  most  often,  and  in  enormous  numbers,  found  intracellularly  situated. 

Hitherto,  no  attention  has  been  paid  to  this  intracellular  habitat  of  Ducrey's 
bacillus,  but  it  doubtless  accounts  for  the  chrouicity  of  the  lesions,  and  the  way 


I 


ULCUS   MOLLE    (SOFT   SORE).  3G7 

in  which  they  resist  anything  but  specific  treatment.  According  to  the  views  of 
present-day  medicine,  one  should  look  upon  this  intracellular  invasion  in  the  light 
of  a  process  of  phagocytosis. 

Let  us  for  a  moment  tixrn  our  attention  to  phagocytosis.  Phagocytosis  has 
been  largely  studied  by  the  behaviour  of  cells  to  foreign  bodies  outside  the  body. 
Following  upon  this,  the  opsonic  index  saw  light,  and  the  protective  capacity  of 
the  body  was  estimated  by  the  number  of  organisms  a  few  leucocytes  outside  the 
body  could  take  up. 

If  we  turn  from  laboratory  experiments  to  the  human  body  and  compare  notes, 
we  find  practically  no  analogy. 

There  is  no  evidence  that,  in  corpore,  tubercle  bacilli  are  destroyed  by 
phagocytosis,  and,  in  sections  of  infected  material,  no  bacilli  are  to  be  found  in 
cells,  except  in  the  so-called  giant  cells  which,  by  the  way,  are  not  single  cells,  but  a 
conglomeration  of  endothelial  cells  which  produce  an  obliterative  endoljanphangitis. 
Taking  those  diseases  in  which  bacilli  are  found  intracellularly  situated,  viz., 
gonococcal  and  meningococcal  infections,  the  intracellular  organisms  are  living  at 
the  expense  of  the  leucocytes,  not  vice  versa.  In  the  case  of  gonorrhoea,  no  doubt 
this  phenomenon  plays  a  part  in  the  chronicity  of  the  disease. 

In  Ulcus  molle,  Ducrey's  bacillus  is  extracellular  ;  in  the  complication  Ulcus 
molle  serpigiyiosum,  which  is  one  of  the  most  chronic  ulcers  known,  the  organisms 
have  become  intracellular.  We  have  another  instance  of  chronicity  and  intracellular 
habitat  of  the  causative  organism  in  the  case  of  rhinoscleroma,  which  is  undoubtedly 
the  same  organism  as  a  certain  form  of  pneumo-bacillus. 

In  protozoal  diseases,  phagocytosis  is  unknown,  the  polymorphonuclear 
leucocyte,  the  phagocytic  cell  par  excellence,  is  not  in  evidence. 

There  can  be  no  doubt  that  phagocytosis  is  purely  a  secondary  phenomenon, 
and  probably  it  merely  consists  in  removing  those  organisms  which  have  been 
killed  by  other  means  {vide  Chapter  XL VIII). 

Not  infrequently,  the  lymphangitis  of  the  penis  which  follows  a  soft  sore  may 
become  adherent  to  the  skin  and  may  ulcerate,  producing  an  even-cut,  freely 
discharging  ulcer,  which  heals  very  quickly  under  treatment.  While  the  soft  sore 
and  bubo  are  still  present,  the  patient  may  develop  on  the  scrotum,  the  thigh,  or 
the  abdomen,  one  or  more  ulcers  which  difier  in  appearance  only  slightly  from 
the  Ulcus  violle  serpiginosum.  The  edges  are  not  so  markedly  undermined,  they 
have  not  the  blue  appearance  of  venous  congestion,  the  surrounding  inflammation 
is  not  so  apparent,  and  the  base  of  the  ulcer  is  not  so  deep.  Such  ulcers  heal  very 
rapidly  under  local  applications  of  camphphenol  and  iodoform,  and  the  Ducrey's 
bacillus  is  always  found  extracellularly  situated. 

2  A 


368  the  biology,  clinical  aspect  and  treatment  of  soft  sore. 

Treatment. 

Great  care  must  be  taken  if  the  sore  is  to  be  cauterised,  since  many 
cauterising  agents  may  set  up  a  phagedaena.  The  worst  ofiender  in  this 
respect  is  diluted  carbolic  acid.  The  concentrated  carbolic  acid  can  be  used  with 
impunity,  and  a  preparation  I  nearly  always  employ  myself  is  camphphenol.  If 
camphor  and  carbolic  acid  crystals  are  pounded  together  in  a  mortar,  a  syrupy 
liquid  results,  to  which  the  name  camphphenol  is  given.  The  sore  should  be  dried 
as  much  as  possible  before  this  caustic  is  applied,  as  this  renders  its  application 
well  nigh  painless.  Cauterisation  by  means  of  zinc  ionisation  quickly  causes  soft 
sores  to  heal,  but  special  apparatus  is  required,  and  it  takes  up  some  time. 

A  good  apparatus  for  ionisation  is  a  Morton's  switchboard.*  This  apparatus 
has  a  rheostat,  and  can  be  worked  from  the  main.  A  2  per  cent,  solution  of  zinc 
sulphate  should  be  applied  to  the  sore,  by  means  of  a  piece  of  soaked  lint  attached 
to  the  negative  electrode.  The  positive  electrode  should  have  a  wide  area,  and 
it  may  be  placed  under  one  buttock.  The  strength  of  the  current  should  be  as 
great  as  the  patient  can  stand,  and  the  apphcation  should  last  about  20  minutes. 

After  cauterisation,  a  powder  should  be  dusted  on,  and  the  following  are  the  three 
I  think  the  best :  Iodoform,  isoform,  and  the  sozoiodolate  of  mercur)%  sodium  or  zinc. 

As  already  stated,  hot  applications  are  extremely  useful,  hot  sitz  baths,  hot 
air  baths,  etc. 

If  the  patient  has  a  tight  foreskin,  and  the  sores  cannot  be  reached,  and  there 
is  ever  the  risk  present  of  phagedaena  ensuing,  the  foreskin  should  be  slit  up,  or 
even  a  circumcision  should  be  performed.  Under  no  other  circrmistances  should 
any  operative  procedure  be  undertaken.  The  wounds  invariably  become  infected, 
and  phagedaena  often  sets  in.  I  once  removed,  widely,  and  under  the  strictest 
antiseptic  precautions,  a  soft  sore  which  had  barely  been  present  for  48  hours,  and 
the  whole  of  the  foreskin  ultimately  became  infected,  and  sloughed. 

Lymphangitis. 
Lymphangitis  is  most  often  seen  on  the  dorsmn  of  the  penis,  but  it  may 
also  occur  along  the  sides.  It  frequently  gives  rise  to  strands,  which  are  to 
be  so  commonly  felt  in  syphilis.  Lymphangitis  ex  ulcere  molH  is  never  so 
hard  as  it  is  in  syphilis  ;  it  is,  moreover,  painful  and  inflamed,  i.e.,  the  skin  over 
it  is  red.  'While  the  lymphangitis  still  persists,  and,  more  rarely,  after  it  has 
vanished,  a  little  swelling  may  appear  anywhere  along  its  course.  This  swelhng  is 
inflammatory,  and  soon  breaks  through  the  skin  covering  it  ;  an  abscess  or  an 
ulcer  forms,  and  quickly  assumes  the  character  of  a  soft  sore.     Such  a  lesion  is 

*  Schall,  Xew  Cavendish  Street. 


ULCUS   MOLLE    (SOFT    SORE).  369 

usually  called  a  bubouulus.     A  bubonulus  may  heal  spontaneously  as  quickly  as 
it  appeared,  or  it  may  spread  and  give  rise  to  a  lesion  like  Ulcus  niolle  serpiginosum. 

Lymphadenitis. 

The  organisms  reach  the  lymphatic  glands  along  the  lymphatics.  They 
may  cause  merely  an  enlargement  of  the  glands,  or  suppuration  in  them. 
The  term  bubo  is  usually  applied  to  the  suppurative  Lymphadenitis  ex  ulcere  niolli, 
and  one  of  the  most  interesting  points  about  it  is  the  fact,  that  a  bubo  may  not 
appear  for  weeks  or  months  after  the  site  of  infection  has  healed  and  has  been 
forgotten.  Such  a  late  bubo  is  very  apt,  in  tropical  countries,  to  be  the  starting 
point  of  an  Ulcus  molle  serpiginosum.  The  retardation  is  very  probably  due  to 
certain  of  the  organisms  having  taken  up  an  intracellular  habitat.  As  is  the  case 
with  most  abscesses,  the  causative  organism  is  not  to  be  found  in  the  pus  ;  hence 
a  negative  search  for  the  streptobacilli,  in  the  discharge  from  an  abscess  in  the 
groin,  is  not  against  the  lesion  being  a  bubo.  If  one  wishes  to  demonstrate  the 
streptobacilli,  it  is  necessary  to  take  a  scraping  from  the  inner  wall  of  the  ab.scess 
cavity.  In  a  large  number  of  cases,  the  pus  from  a  bubo  is  sterile ;  in  the  remainder, 
there  is  a  mixed  infection. 

The  pathology  of  a  bubo  is  very  simple,  but  in  order  that  the  best  means  of 
treating  it  may  be  adopted,  it  is  necessary  to  understand  it  thoroughly. 

At  first,  several  glands  become  infected  with  the  streptobacilli.  In  one  gland 
only  does  the  inflammation  proceed  to  suppuration.  While  the  process  is  maturing, 
the  gland  approaches  the  skin,  and  becomes  adherent  to  it.  Either  one  of  two 
courses  is  now  open.  The  abscess  bursts  through  the  skin,  or,  laterally,  into  the 
interglandular  tissue.  If  the  route  is  the  latter,  then  the  suppurative  process  is 
almost  bound  to  reach  to,  and  to  implicate,  the  neighbouring  glands. 

If  the  abscess  bursts  through  the  skin,  the  lateral  walls  are  usually  strong,  and 
they  prevent  infection  of  the  interglandular  tissue.  Hence  it  can  be  readily  seen 
that  the  employment  of  operative  measures,  before  the  bubo  has  pointed,  or,  in 
other  words,  before  the  lateral  walls  have  been  perfected,  may  easily  allow  the 
infection  to  become  interglandular. 

Incision  should  be  delayed  as  long  as  possible,  and  recourse  should  be  had  to 
cold  applications,  in  particular  to  evaporating  lotions — 

R  Plumbi  subacetat.         . .         . .         . .         gi'-  x. 

Liq.  ammon.  fort.  . .         . .         . .         iii^v 

Spir.  vini.  rect.  . .         . .         . .         . .         5] 

Solut.  ajumin.  acetat.    ..         .  .3  per  cent,  ad  ,5] 

2  A  2 


370  THE   BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   SOFT    SORE. 

and  the  observer  will  be  astonished  to  find  how  many  resolve.  The  overlying  skin 
becomes  pink  and  tender,  before  any  pus  has  formed  in  the  gland. 

Owing  to  the  fact  that  the  pus  originates  in  the  substance  of  one  gland  only, 
it  follows  that  the  quantity  evacuated  on  incision  will  fall  considerably  short  of 
the  quantity  expected,  and  it  is  likewise  equally  obvious  that  only  a  tiny  incision 
is  required  to  drain  the  bubo. 

A  long  incision  will  break  through  the  barriers  formed  by  the  lateral  walls, 
with  the  result  that  the  interglandular  tissue  is  bound  to  become  infected.  A  wide 
incision  also  exposes  other  glands,  which  are  nearly  always  removed  by  the  surgeon, 
for  reasons  unknown. 

In  the  first  place,  removal  of  all  the  lymphatic  glands  in  one  inguinal  region 
is  not  a  suuple  matter,  and  permanent  oedema  of  the  corresponding  half  of  the 
scrotum  is  a  complication  quite  liable  to  result. 

Moreover,  the  bigger  the  incision,  the  bigger  the  wound  which  has  to  granulate 
up  from  the  bottom,  with  the  result  that  a  patient  may  be  obliged  to  be  absent 
from  his  work  for  six  months  or  more. 

As  the  vitality  of  the  skin  over  a  bubo  is  often  very  much  impaired,  any  other 
procedure  than  a  nick  with  a  bistoury  may  destroy  it  altogether,  and  then  the 
complicating  factor  of  phagedaena  has  to  be  dealt  with. 

A  nick  of  I  to  1  centimetre  should  be  made  where  the  abscess  is  pointing,  or 
where  the  skin  is  softest.  The  pus  should  then  be  expressed,  and  the  cavity  lightly 
washed  out  with  saline.  No  powerful  antiseptic  should  be  used,  owing  to  its  tendency 
to  set  up  gangrene  in  the  edge.  A  fine  piece  of  gauze  should  be  left  in  the  opening, 
one  of  the  three  powders  above  mentioned  should  be  dusted  on,  and  the  wound 
dressed  daily  until  it  is  healed,  which  is  usually  a  matter  of  days  only. 

1  Ducrey  (1889),  "  Giorn.  ital.  d.  mal.  Ven.  e.  d.  pelle,"  xxx,  377. 
=  Ducrey  (1889),  "  Monatsh.  f.  prakt.  Derm.,"  ix,  387. 
^  Ducrey  (1895),  "  Monatsh.  f.  prakt.  Derm.,"  xxi,  57. 

*  Tomasczewski  (1912),  "  Handbuch  d.  Gesehlechts.  Krankheiten,"  ii,  613. 
^  Umia  (1895),  "  Monatsh.  f.  prakt.  Derm.,"  xxi,  61. 

«  NicoUe  (1906),  "  Presse  m6d.,"  265. 

'  Dubreuilh  (1893),  "Arch,  clin.  de  Bordeaux,"  ii,  500,  513. 

*  McDonagh  (1914),  "  Brit.  Journ.  of  Derm.,"  xxvi,  1. 


CHAPTER  XXXII. 
GONOREHOEA. 

The  gonococcus  was  discovered  by  Neisser^  in  1879.  It  is  a  diplococcus,  and  it 
varies  somewhat  in  morphology,  according  to  the  conditions  under  which  it  has 
grown.  The  diplococcal  character  is  more  constant  in  films  made  from  human 
material  than  in  those  made  from  cultures.  In  pus,  the  gonococcus  is  more  coSee- 
bean  shaped,  concave  at  its  inner  end,  and  rather  pointedly  convex  at  its 
outer  end. 

The  gonococcus  stains  very  well  with  aniline  dyes,  and,  as  every  observer  has, 
when  studying  its  staining  properties,  left  behind  him  a  special  method  which  goes 
by  his  name,  and  as  the  same  thing  has  happened  with  the  media  on  which  it  has 
been  grown,  we  have  a  legion  of  stains  and  culture  media,  all  of  which  have  been 
specially  recommended.  In  view  of  this,  I  will  confine  myself  to  mention  those  which 
have  been  generally  found  to  be  the  simplest  and  most  serviceable. 

So  far  as  the  methods  of  staining  are  concerned,  onl}^  three  need  be  mentioned. 
The  first  place  must  be  given  to  Gram's  method,  becau.se  the  gonococcus  is  a  Gram 
negative  organism,  then  to  Pappenheim's^  method,  which  gives  a  very  pretty 
picture  ;  and,  finally,  to  v.  Leszczynsky's^  method,  M'hich  is  stated  to  stain  the 
gonococci  in  a  specific  manner. 

Grams  Method. — 1.  A  thin  film  is  made  and  fixed  by  heat,  and  then  stained  for 
one  minute  in  carbolgentianviolet.  The  best  carbol  gentian  violet  mixture  is  that 
of  Czaplewski,*  as  it  keeps  well': — 

Sat.  alcoh.  sol.  of  gentian  violet  . .         . .         . .     10  parts. 

2 . 5  per  cent.  aq.  sol.  of  carbolic  acid     . .         . .         . .     90  parts. 

Washing  the  film  quickly  before  staining  with  a  1  per  cent,  solution  of  acetic 
acid  enhances  the  staining  action  of  the  carbol  gentian  violet. 

2.  Pour  off  stain. 

3.  Cover  film  with  iodine  potassium  iodide  solution  (1:2:  300)  for  one  minute, 

4.  Pour  iodine  solution  off. 


372  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT    OF   GONORRHOEA. 

5.  Wash  with  absolute  alcohol,  till  superfluous  stain  has  been  washed  away. 

6.  Wash  with  water. 

7.  Counterstain  with  a  weak  aqueous  solution  of  safranin  or  carbol  fuchsin. 

8.  Wash  with  water. 

9.  Dry. 

Pappenheim's  Method. — The  film  should  be  stained  for  not  less  than  five  minutes. 
Over-staining  is  impossible  in  the  following  solution  : — 

Methyl  green      ..          ..          ..  ..     O'lSc.c. 

Pyronin  ..          ..         ..         ..  ..     0'45c.c. 

Alcohol    . .         . .         . .         . .  . .     2'5    c.c. 

Glycerine            ..          ..         ..  ..  20'0   c.c. 

2  per  cent.  aq.  sol.  of  carbolic  acid  ad  100  c.c. 

The  stain  can  be  bought  ready  prepared,  and  is  known  as  Unna's  carbolpyronin 
methyl  green  solution.     The  stain  does  not  keep  indefinitely,  as  the  pjTonin  tends  to 
disappear,  hence  I  have  added  rather  more  pyronin  in  the  above  formula  than  in  that 
usually  given.    After  staining,  the  film  should  be  washed  with  water,  and  then  dried. 
By  this  method  all  organisms  stain  red,  the  gonococci  staining  especially  brilliantly  ; 
the  protoplasm  of  cells  stains  pink  to  red,  the  nuclei  stain  green,  and  the  nucleoli 
red.     Pappenheim  himself  advocates  counter-staining  with  orange-G.,  but  this  does 
not  appear  to  me  to  be  necessary. 

V.  Leszaynsh/s  Method. — 1.  The  film  is  stained  for  one  minute  in  the  following 
thionin  solution  : — 

Sat.  aq.  sol.  of  thionin  . .  . .  . .     10  c.c. 

Acid,  carbol.  liq.  . .         . .         . .      2  c.c. 

Aq.  dist 88  c.c. 

2.  Wash  with  water. 

3.  Treat  for  one  minute  in  the  following  picric  acid  solution  : — 

Sat.  aq.  sol.  of  picric  acid. 

1  :  1000  aq.  sol.  of  potassium  hydrate,  aa.  seq.  partes. 

4.  Wash  with  water. 

5.  Treat  for  five  seconds  with  absolute  alcohol. 

6.  Wash  with  water. 

Only  the  intracellular  gonococci  stain  black,  the  other  bacteria  yellow-red  to 
red.  For  staining  gonococci  in  section,  the  method  described  in  Chapter  VI.  with 
pyronin  and  methyl  green  is  the  best.     The  tissue  is  best  fixed  in  absolute  alcohol. 

For  culturing  the  gonococcus,  I  have  found  the  following  two  media  meet  all 
requirements. 


UNCOMPLICATED    GONORRHOEA.  373 

Ascites  fluid,  or  pleural  fluid  agar  and  blood  agar. 

To  make  ascites  fluid  agar,  all  that  is  necessary  is  to  cool  melted  agar  to  45°  C, 
and  then  add  sterile  ascites  fluid  in  the  proportion  of  1  in  5. 

To  make  blood  agar,  it  is  only  necessary  to  cover  the  agar  with  a  thin  layer 
of  freshly-drawn  sterile  blood. 

The  optimum  temperature  at  which  the  organism  grows  is  between  34°  C. 
and  37°  C.  The  colonies  begin  to  make  their  appearance  within  twenty-four  hours. 
They  grow  rapidly  for  two  to  three  days,  and  then  begin  to  die,  unless  other  tubes 
are  inociflated.  The  colonies  are  about  the  size  of  a  pin's  head  and  discrete.  They 
are  circular,  but  the  edge  is  serrated.  They  are  more  or  less  transparent.  They 
look  like  tiny  areas  of  slime,  and  appear  to  be  finely  granular. 

The  colonies  are  sensitive  to  cold,  and  quickly  die  if  the  medium  is  too  dry  or 
too  overgrown  with  other  organisms,  and  the  gonococcus  does  not  like  changes  of 
temperature. 

Incubation  Period. 

The  usual  incubation  period  varies  from  two  to  eight  days.  Occasionally 
it  may  be  very  much  longer.  The  longest  I  have  ever  known  was  just  over  six 
weeks.  In  all  infectious  diseases,  especially  is  this  the  case  in  gonorrhoea,  several 
factors  are  at  work,  which  influence  the  infection.  There  is  the  resistance 
of  the  patient  to  be  considered,  the  strain  of  the  organism  with  which  he  is 
infected,  the  quantity  of  infected  material  which  is  implanted  on  the  patient, 
and  the  area  over  which  it  is  spread.  Any  one  of  these  may  cause  a  variation  in  the 
length  of  the  incubation  period.  In  a  patient  who  has  had  the  disease  before  and  has 
been  cured,  the  incubation  period  is  more  likely  to  be  shorter  than  usual,  and  in  a 
patient  who  has  had  the  disease  before  and  who  is  now  suffering  from  a  recurrence, 
the  incubation  period  may  be  only  twelve  or  twenty-four  hours. 

The  Manner  of  Spread  of  the  Organisms. 

When  gonococci  first  are  implanted  upon  the  urethral  mucous  membrane,  they 
multiply  extracellularly,  and  produce  no  pus.  In  a  few  days,  polymorphonuclear  leuco- 
cytes reach  the  lumen  of  the  urethra,  via  the  spaces  between  the  epithelial  cells,  from 
the  blood-vessels  in  the  subepithelial  tissue.  Then  the  organisms  become  intracellular, 
and,  in  my  opinion,  live  and  multiply  at  the  expense  of  the  polymorphonuclear  leuco- 
cytes. From  this  time  onwards,  pus  is  formed,  and  the  gonococci  wander  in  between 
the  epithelial  cells,  possibly  in  search  of  the  polymorphonuclear  leucocytes,  as  they 
are  on  their  way  to  the  surface.  As  time  progresses,  the  number  of  gonococci 
diminishes,    and    their    destruction    is    brought    about    in    tliree    ways:     (1)    by 


374  THE    BIOLOGY,    CLINICAL    ASPECT  '  AND   TREATMENT   OF   GONORRHOEA. 

antibodies    circulating   in   the   blood   stream  ;     (2)  by   chemical   substances  which 
emanate  from  the  epithelial  cells  ;   (3)  by  the  growth  of  other  organisms. 

From  almost  the  very  start,  the  gonococci  may  reach  the  subepithelial  tissue, 
and  may  even  enter  the  blood  stream  and  give  rise  to  n^etastases.  I  once  liad  a  case 
which  developed  acute  polyarthritis  and  tenosynovitis  on  the  seventh  day  of  the 
infection,  while  the  infection  was  still  limited  to  the  anterior  portion  of  the  urethra. 
It  is  highly  probable  that  the  production  of  antibodies  occurs  very  early  in  the 
disease,  since  the  administration  from  the  very  start  of  potent  vaccines,  which 
increase  the  antibody  content  of  the  serum,  does  undoubtedly  influence  the  future 
course  of  the  infection.  It  cannot  be  proved  when  antibodies  are  first  formed,  as 
we  have  no  test  which  can  be  applied  in  gonorrhoea  to  detect  infinitesimal  quan- 
tities.    The  complement  fixation  test  is  not  nearly  delicate  enough. 

The  reason  why  I  think  the  epithelial  cells  can  destroy  gonococci,  is  because 
some  individuals  seem  more  or  less  immune  to  gonorrhoea,  because  the  vaginal 
mucous  membrane  of  adidts  is  practically  never  affected  ;  while  that  of  young  girls 
IS  especially  prone  to  be  affected,  and  because  both  the  nasal  mucous  membrane 
and  the  buccal  mucous  membrane  are  very  seldom,  if  ever,  involved.  The  secretion 
of  the  epithelial  cells  in  the  different  localities  must  have  varying  anti-gonococcal 
properties.  Considering  we  are  obliged  to  use  strong  antiseptics  in  the  treatment 
of  gonorrhoea,  it  would  be  well  worth  while  to  pay  some  attention  to  the  chemistry 
of  the  secretion  from  the  nasal  and  buccal  mucous  membranes,  with  the  hope  of 
finding  a  non-irritative  substance  which  would  destroy  the  gonococci. 

The  advent  of  other  organisms  often  means  the  destruction  of  the  gonococci. 
Although  gonococci  may  be  found  in  urethral  abscesses,  prostatic  abscesses,  in  the 
pus  from  a  suppurative  epididymitis  and  adenitis,  it  is  far  more  common  to  fail 
to  find  the  gonococcus,  or  even  to  culture  it.  In  probably  over  90  per  cent,  of  the 
suppurative  lesions  primarily  caused  by  the  gonococcus,  only  extraneous  organisms 
are  to  be  found,  and,  in  very  many  of  these  cases,  the  secondary  infection  often 
results  in  the  spontaneous  cure  of  the  gonorrhoea. 

After  the  organisms  have  been  multiplying  for  some  time  in  the  anterior  part 
of  the  urethra,  they  gradually  extend  backwards,  and,  usually  while  the  condition 
is  still  acute,  reach  the  posterior  part  of  the  urethra.  Occasional!}-  the  inflammation 
may  be  chronic  before  the  posterior  part  of  the  urethra  is  affected,  and  the  patient 
may  have  signs  of  a  chronic  prostato-urethritis,  although  the  posterior  infection 
has  never  been  acute. 

Once  the  posterior  part  of  the  urethra  is  affected,  there  is  more  likehhood  of  the 
organisms  getting  into  the  blood  stream,  and  of  their  giving  rise  to  metastases ; 
still  more  is  this  the  case  when  the  prostate  is  implicated. 


XJNCOMPLICATED    GONORRHOEA.  375 

The  organisms  spread  up  the  prostatic  ducts,  and  infect  the  prostate,  in  the 
majority  of  the  cases  in  which  the  disease  spreads  to  the  posterior  part  of  the 
urethra.  The  organisms  may  also  spread  up  the  seminal  ducts,  reach  the  vesiculae 
seminales,  which  they  frequently  infect.  From  here  they  spread  along  one  or  both 
vasa  deferentia,  which  usually  escape  infection,  for  a  reason  not  yet  Imown,  and 
reach  one  or  both  testicles,  which  quickly  succumb.  Hence  it  follows,  that  it  is 
almost  invariably  the  lower  pole  of  the  epididjTuis  which  is  involved. 

Although  the  organisms  may  reach  the  bladder  by  direct  extension  backwards 
of  the  pus,  from  the  prostatic  portion  of  the  urethra,  the  bladder  very  rarely  is 
infected. 

The  gonococcus,  or  its  toxine,  may  produce  lesions  in  almost  any  part  of  the 
body.  Lesions  produced  by  the  gonococcus  itself  are  metastatic,  and  those  produced 
by  its  toxine  are  toxic,  and  it  is  by  no  means  always  easy  to  say  whether  such  and 
such  a  lesion  is  a  metastatic  or  a  toxic  one.  Observers  are  still  very  much  divided 
in  their  opinions  as  to  whether  the  so-called  rheumatic  iritis  is  due  to  the  gonococcus 
or  to  the  gonotoxine.  These  various  metastatic  and  toxic  lesions  will  be  dealt  with 
in  a  separate  chapter,  after  the  local  infection  has  been  described,  and,  before  the 
local  infection  is  discussed,  it  would  be  as  well  to  make  a  few  remarks  upon  the 
anatomy  of  the  part. 

Anatomy. 

The  male  urethra  is  divided  into  pendulous,  bulbous,  membranous,  and 
prostatic  portions.  Of  these,  the  two  anterior — which  lie  in  front  of  the 
triangular  ligament — are  surrounded  by  cavernous  tissue  ;  the  two  latter — which 
lie  behind  that  ligament,  by  muscular  tissue.  The  membranous  portion  is  surrounded 
by  niuscle  fibres,  contraction  of  which  compress  its  lumen,  and  so  cause  that 
retention  and  straining  which  is  typical  of  a  posterior  infection.  Since  the  two 
anterior  portions  of  the  urethra  are  surrounded  by  cavernous,  and  the  two  posterior 
by  muscular  tissue,  we  can  make  a  clinico-anatomical  distinction,  and  assert  that 
an  anterior  urethritis  is  an  inflammation  of  cavernous  tissue,  while  a  posterior 
urethritis  is  an  inflammation  of  muscular  tissue,  the  triangular  ligament  being  the 
anatomical  demarcation  between  the  two  clinical  types. 

Symptoms. 

The  first  signs  noted  are,  that  a  few  hours  after  passing  water,  the 
urethra  contains  a  greyish-white  viscid  fluid,  its  meatus  is  reddened  and  swollen, 
but  the  urine  is  clear.  A  few  days  later,  the  secretion  thickens  and  is  stained  yellow, 
or  green,  or  blackish  from  haemorrhage  of  the  inflamed  mucous    membrane.     It 


376  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   GONORRHOEA. 

forms  a  "  bead  "  over  the  orifice  iu  the  morning.  The  passage  of  urine  causes  that 
burning  sensation  described  by  a  coster  as  "  like  passing  red  hot  pins  and  needles." 
At  night  erections  are  frequent,  and  excruciatingly  painful. 

The  inflammation,  which  begins  at  the  orifice,  now  extends  backward  along 
the  penile  portion  ;  the  danger  and  severity  of  the  attack  depend  upon  the  extent  of 
spreading.  The  patient  now  runs  an  evening  temperature,  and  cannot  sleep  on 
account  of  painful  erections. 

By  the  end  of  the  second  week,  the  infection  has  travelled  backward  as  far  as 
the  bulbo-membranous  junction.  The  bulbous  portion  being  inflamed,  pressure 
on  the  i^erinaeum  causes  pain.  The  tenderness  or  non-tenderness  of  the  perinaeum 
gives  a  useful  key  to  the  extent  of  the  inflammatory  process. 

At  this  stage  two  courses  are  possible.  Either  the  inflammation  is  localised 
to  the  penile  and  bulbous  portions  in  front  of  the  triangular  ligament,  and  con- 
stitutes an  anterior  urethritis  only ;  or  it  may  spread  back  to  the  membranous  and 
prostatic  portions,  constituting  a  posterior  urethritis. 

In  anterior  urethritis,  the  symptoms  begin  to  subside  at  the  end  of  the  third 
week,  and  have,  with  the  exception  of  a  slight  tingling  sensation  on  micturition, 
disappeared  by  the  end  of  the  fifth.  The  discharge  is  less  in  amount,  thinner,  and 
whiter  than  that  of  a  posterior  urethritis.  So  long  as  there  is  discharge,  the  urine 
appears  turbid  when  passed  ;  but  it  forms  a  deposit  on  standing.  The  discharge 
consists  of  epitheUal  and  pus  cells,  which  take  the  form  of  threads  and  flakes  on 
account  of  the  acidity  of  the  urine.  About  75  per  cent,  of  gonorrhoea  patients  suffer 
from  a  posterior  luethritis.  The  symptoms  which  distinguish  a  posterior  from  an 
anterior  infection  are  frequency  of  micturition  during  working  hours,  but  not 
necessarily  at  night.  This  frequency  is  accompanied  by  strangury — a  spasm  of 
the  sphincter — which  causes  either  complete  retention,  or  the  passage  of  urine  in 
drops  after  long  straining.  Haematuria  is  common,  the  blood  appearing  with  the 
last  drops  of  urine.  Generally  the  patient  complains  of  a  burning  or  tickhng 
sensation  about  the  rectum  and  anus. 

The  discharge  both  .stiffens  and  stains  linen  ;  but  so  does  the  pus  from  a 
balanitis,  so  that,  if  the  glans  penis  be  inflamed,  the  patient  must  draw  back  the 
foreskin  and  wipe  the  meatus  before  micturition,  or  the  usual  "  two  glass  test " 
will  be  useless.  The  two  glass  test  should  be  carried  out  in  every  case.  The  patient, 
whose  bladder  must  be  nearly  full,  is  made  to  micturate  into  two  test  glasses,  and 
the  contents  are  compared.  Into  the  first  he  passes  a  few  ounces  ;  into  the 
second  the  remainder.  If  the  contents  of  the  first  glass  be  thick,  he  has  an  acute 
anterior  urethritis  ;  if  the  contents  of  the  second  be  also  thick,  then  he  has  a  posterior 
urethritis. 


UNCOMPLICATED    GONORRHOEA.  377 

The  pus  of  anterior  "  cavernous  "  urethritis,  having  nothing  to  keep  it  back, 
discharges  freely  at  the  meatus,  while  any  that  remains  in  the  canal  will  be  flushed 
out  by  the  first  flow  of  urine.  That  first  portion  of  urine  must,  therefore,  be  clouded, 
while  the  remainder  may  be  clear.  On  the  contrary,  the  pus  of  a  posterior 
"  muscular  "  urethritis  is  shut  in,  between  the  sphincter  prostatae,  on  the  one  hand, 
and  the  compressor  urethrae,  on  the  other. 

When  urine  has  not  been  passed  for  some  hours,  the  amount  of  pus  secreted 
becomes  greater  than  the  space  can  contain.  It  must  then  go  in  the  direction  of 
least  resistance,  which  is  through  the  prostatic  sphincter  into  the  bladder,  clouding 
the  urine  therein.  If  water  be  now  passed  into  two  glasses,  both  will  be  thick,  but 
the  former  the  more  so,  as  it  contains  also  that  pus  which  was  left  in  the  urethra. 
Should  the  quantity  of  pus  formed  be  not  greater  than  the  urethra  can  accommodate, 
there  will  be  no  regurgitation,  and  the  second  glass  will  be  quite  clear. 

The  morning  urine  is  the  best  on  which  to  try  this  test,  as,  owing  to  the  longer 
retention  of  urine,  more  pus  is  formed,  and  therefore  regiirgitation  is  more  likely. 
Some  points  about  morning  urine  should  be  noted.  Pus  dissolves  in  urine  owing 
to  a  trace  of  pepsin.  Hence,  should  the  morning  urine  be  first  examined  in  the 
afternoon,  a  wrong  idea  may  be  formed.  The  presence  of  pepsin  also  accounts 
for  the  occasional  loss  of  an  albumin  reaction  in  cases  of  slight  nephritis,  being 
present  one  day  and  absent  the  next,  and  also  for  the  disappearance  of  casts.  Pus 
dissolves  more  C[uickly  in  morning  than  day,  warm  than  cold,  acid  than  alkaline 
urines.     Bacillus  coli  communis  is  also  said  to  have  the  power  of  dissolving  albumin. 

A  very  simple  method  of  telling  whether  the  posterior  part  of  the  urethra  is 
affected,  should  the  test  already  mentioned  fail,  is  to  pass  a  catheter  as  far  as  the 
triangular  ligament,  and  wash  out  the  anterior  part  of  the  urethra  with  a  weak 
solution  of  boracic  acid.  This  is  collected  into  a  glass,  and  examined.  Such  a  pro- 
cedure washes  out  all  the  threads  which  are  in  the  anterior  part  of  the  urethra. 
The  patient  is  then  made  to  pass  his  water  into  another  glass.  Should  any  threads 
be  seen,  they  must  have  come  from  the  posterior  part  of  the  urethra. 

In  cystitis  both  urines  are  thick,  but  the  second  thicker  than  the  first,  because 
the  pus  produced  in  the  bladder  settles  to  the  bottom  thereof,  and  is  passed  last. 
Cystitis  may  be  diagnosed  from  posterior  urethritis,  when  both  do  not  occur  together, 
for  the  urine  is  usually  alkaline  in  cystitis,  acid  in  urethritis.  Microscopically, 
one  finds  the  typical  transitional  bladder  epithelial  cells  in  cystitis,  in  which,  too, 
pain  in  the  small  of  the  back  and  in  the  region  of  the  symphysis  is  common. 

Two  pitfalls  wait  for  him  who  would  diagnose  posterior  urethritis  : — 

(a)  The  thickness  of  urine  may  be  due  to  phosphates,  which  clear  on  adding 
dilute  acetic  acid,  or  to  oxalates. 


378  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   GONORRHOEA. 

Patients  with  sexual  neurasthenia  are  very  prone  to  have  phosphatiiria  and 
oxaluria.  During  the  fruit  season,  phosphaturia  is  very  common,  and  patients  who 
have  had  a  meal  devoid  of  meat,  and  who  have  partaken  freely  of  green  vegetables, 
and  who  have  drunk  large  quantities  of  effervescent  lemonade,  are  almost  certain 
to  have  phosphaturia  for  some  hours  afterwards. 

(6)  It  is  diificidt  to  get  patients  to  do  the  two-glass  test  carefully.  If  you 
suspect  the  patient  of  carelessness,  ask  him  how  often  he  gets  iip  at  night  to  pass 
water.  Nocturnal  frequency  is  usual  in  posterior  urethritis  and  cystitis,  not  so 
in  anterior  urethritis. 

Chronic  Urethritis. — The  characteristic  picture  of  chronic  urethritis  is  morning 
discharge,  sticking  together  of  the  lips  of  the  urethral  orifice,  cloudiness  of,  or  threads 
in  the  urine ;  but  one  must  remember  that  there  are  patients  who  show  all  these 
features,  and  yet  they  have  not  got  gonorrhoea,  but  only  its  after  effects.  After  chronic 
urethritis,  there  occurs  a  collection  of  flat  epithelial  cells  in  the  recently  diseased 
areas,  and  these  cells  desquamate  to  such  an  extent  as  to  produce  a  milky  discharge 
and  threads.  The  differential  diagnosis  lies  in  the  fact  that,  microscopically,  these 
threads  show  only  flat  epithelial  cells  and  only  a  few  pus  cells. 

There  is  one  great  difference  between  acute  and  chronic  gonorrhoea.  In  acute 
gonorrhoea,  the  inflammation  is  diffuse  and  spread  over  the  greater  part  of  the 
urethral  mucous  membrane.  In  chronic  gonorrhoea,  it  affects  hmited  areas.  There 
are  two  stages  in  chronic  gonorrhoea.  One,  in  which  there  is  a  connective  tissue 
hyperplasia  with  hyperaemia,  swelling  of  mucous  membrane,  catarrhal  desquamation 
of  epithehum,  especially  of  Littre's  glands.  The  other,  in  which  connective  tissue 
iscovered  by  an  overgrowth  of  flat  epithelial  cells. 

The  first  stage  might  be  called  subacute  urethritis,  and  is  not  limited  to  definite 
areas.  The  second  stage  may  be  called  the  chronic  stage.  The  two  stages  admit 
of  differentiation,  since  in  the  former  the  catarrh  of  the  mucous  membrane  clouds 
the  urine,  whereas,  in  the  chronic  form,  the  urine  is  clear  and  contains  threads 
only. 

Inflammation  maj-  spread  under  the  mucous  membrane,  and  produce,  if  it 
spreads  forward,  peri-urethritis  or  cavernitis  ;  or,  if  it  spreads  backward,  pros- 
tatitis. The  diagnosis  between  superficial  anterior  chronic  urethritis  and  the  deep 
form  must  be  made  with  Otis's  urethrometer,  with  a  bougie  a  boule,  or  with  a 
Kollmann's  dilator.  Superficial  inflammation  causes  no  stricture;  but  the  deep  form, 
which  affects  cavernous  tissue,  quickly  reduces  elasticity  and  dilatability,  and  so 
causes  broad  strictures. 

The  diagnosis  of  urethritis  is  not  a  difficult  matter.  In  the  acute  and  sub- 
acute forms,  it  is  very  easy  to  tell,  either  by  the  two  glass-test  or  by  the  irrigation 


UNCOMPLICATED    GONORRHOEA.  379 

test,  whether  the  infection  has  reached  the  distal  side  of  the  triangular  ligament  or 
not.  In  the  chronic  form,  it  is  not  so  easy,  as  both  the  tests  just  mentioned  may 
fail  to  give  an  accurate  result.  One  can  ascertain  for  certain  whether  one  is 
dealing  with  a  chronic  anterior  or  a  chronic  posterior  urethritis,  by  an  endoscopic 
examination  of  the  urethra.  There  are  two  forms  of  endoscope,  one  with  which 
you  can  see  the  anterior  portion  of  the  urethra  only,  and  the  other  which  allows  a 
view  of  the  whole  urethra. 

An  endoscopic  examination  of  the  anterior  part  of  the  urethra  is,  to  all  intents 
and  purposes,  never  required.  If  the  endoscope  is  needed  at  all,  it  is  for  an 
examination  of  the  posterior  part  of  the  urethra,  as  other  tests  used  for  diagnosis 
of  a  chronic  posterior  urethritis  may  fail.  An  endoscopic  examination  is  needed, 
then,  only  in  cases  of  chronic  posterior  urethritis.  Many  cases  of  chronic  posterior 
urethritis  are  complicated  by  a  narrowing  of  the  urethra,  which  prevents  the  instru- 
ment from  being  passed,  and,  in  the  majority  of  cases  of  chronic  posterior  urethritis, 
the  prostate  is  implicated,  and  the  prostatitis  is  a  more  serious  condition  than  the 
chronic  urethritis.  Prostatitis  cannot  be  diagnosed  by  an  endoscopic  examination, 
only  by  a  digital  examination  jper  rectum. 

Assuming  that  an  endoscopic  examination  informs  the  observer  that  the 
patient  is  suffering  from  a  chronic  posterior  urethritis,  the  observer  is  no  better 
off,  as  the  treatment  of  chronic  urethritis  is  the  same,  whether  the  inflammatory 
process  is  limited  to  the  anterior  or  to  the  posterior  part  of  the  urethra.  As  a  chronic 
anterior  urethritis  is  a  very  rare  condition,  one  will  not  be  far  wrong  in  diagnosing 
every  case  of  chronic  urethritis  as  one  of  chronic  posterior  urethritis — indeed,  the 
word  "  posterior  "  becomes  superfluous,  and  the  mere  mention  of  chronic  urethritis 
will  convey  the  idea  that  the  posterior  part  of  the  urethra  is  affected,  and,  in  nine 
cases  out  of  ten,  the  prostate  is  also  affected.  Posterior  endoscopy  is  far  from  being 
a  simple  manoeu\Te  ;  it  is  often  a  very  dangerous  one,  as  time  after  time  I  have  seen 
the  patient's  condition  very  much  aggravated  by  its  use.  Posterior  endoscopy  has 
its  adherents,  aiid  Wossidlo's  new  pattern  urethroscope,  through  which  treatment 
can  be  applied  to  the  spot  affected,  has  in  certain  quarters  met  with  a  great  reclame 

I  can  honestly  say  that  I  have  never  yet  met  a  case  which  has  been  cured,  although 
the  operator  may  have  pronounced  him  to  be  so,  by  endoscopic  treatment,  and  I  have 
seen  many  made  very  much  worse.  Many  post-graduate  courses  are  given  in 
urethroscopy  on  the  Continent,  and  I  have  frequently  noticed  that  many  of  the 
instructors  never  use  the  urethroscope  on  their  private  patients,  unless  it  be  to 
impress  them. 

Summing  up,  I  am  of  the  opinion  that  urethroscopy  is  only  an  infinitesimal 
aid  to  diagnosis,  and  no  guide  as  to  treatment,  and  some  of  the  most  chronic  cases 


380  THE    BIOLOGY,    CLINICAL   ASPECT    AND    TREATMENT    OF   GONORRHOEA. 

of  gonococcal  urethritis  I  have  ever  seen  have  been  kept  going,  by  use  of  the 
urethroscope. 

The  more  cases  of  chronic  urethritis  I  see,  the  more  I  am  beginning  to  realise 
that,  not  only  have  many  of  them  been  caused  by  too  much  treatment,  but  that 
many  are  kept  in  being  by  too  much  treatment,  or  by  too  drastic  an  administration 
of  it. 

Why  is  chronic  urethritis  so  difficult  to  cure  ?  For  the  simple  reason  that 
the  gonococci  have  invaded  the  sub-epithelial  tissue.  Broadly  speaking,  local  treat- 
ment is  not  going  to  have  much  influence  upon  these  sub-epithelial  gonococci ; 
cauterisation  of  the  surface  does  not  reach  them,  nor  does  cauterisation  of  a  follicle, 
should  there  be  proof  that  the  gonococci  had  obtained  entrance  to  the  connective 
tissue  via  a  follicle.  Too  much  treatment,  and  too  drastic  treatment,  i.e.,  the  use  of 
too  strong  solutions  of  antiseptics,  cause  inflammation.  If  the  gonococci  are  not 
killed  directly,  and  in  most  cases  they  are  not,  the  effect  of  inflammation  thus 
caused,  is  to  destroy  the  host's  local  protective  power,  which  will  enable  the  para.sites 
to  develop  at  their  host's  expense,  and  it  will  also  lay  open  a  path  to  a  secondary 
infection. 

Influence  op  Secondary  Infection. 

We  do  not  yet  realise  in  full  the  significance  which  the  secondary  infection  has  in 
cases  of  chronic  urethritis,  so  it  would  be  as  well  to  go  into  the  question  somewhat 
fully  ;  but,  before  doing  so,  I  should  like  to  draw  the  reader's  attention  to  the 
similarity  which  exists  between  gonococci  situated  in  sub-epithelial  tissue  and  a 
piece  of  buried  septic  silk  after  an  operation.  In  the  former,  the  gonococci  have 
to  be  killed,  and  in  the  latter  the  silk  has  to  be  got  rid  of,  or  the  fistula  caused  by 
it  will  never  close.  No  surgeon  would  dream  of  cauterising  the  opening,  or  even 
the  canal  of  the  fistula,  and  j^et  it  is  recommended  to  adopt  this  treatment  in  the 
gonococcal  case.  One  method  of  getting  the  piece  of  silk  is  to  enlarge  the  opening ; 
dilating  the  urethra  will  also  often  allow  one  to  reach  the  gonococci  with  a  mild 
antiseptic.  In  some  cases,  the  silk  comes  away  of  its  own  accord,  and  in  some  cases 
the  gonococci  die  out.  Fortunately,  in  the  gonococcal  case,  we  can  attack  the  parasites 
from  behind,  by  increasing  the  protective  power  of  the  host  with  vaccines — a  method 
which,  in  the  case  of  the  silk,  is  not  applicable. 

Eeturning  now  to  the  influence  of  the  secondary  infection  in  cases  of  chronic 
urethritis. 

The  limits  of  the  role  played  by  a  secondary  infection  in  chronic  prostato- 
urethritis  are  far  from  being  ascertained,  but  one  fact  is  certain,  and  that  is,  that 
many   of   the   cases   of   supposed   chronic   gonococcal   urethritis,   which   resist  all 


UNCOMPLICATED    CJOXORRHOEA.  381 

treatment,  are  due  to  a  secondary  infection,  and  they  will  get  well  if  treatment 
is  suspended. 

The  point  that  now  arises  is,  how  a  chronic  urethritis  of  gonococcal  origin  can 
be  distinguished  from  that  caused  by  a  secondary  infection. 

If  the  patient  seeks  advice,  and  you  learn  that  he  has  had  little  or  no  treatment, 
the  chances  are  that  the  chronic  urethritis  is  still  due  to  gonococci. 

If,  on  the  other  hand,  he  has  been  well  treated,  and  the  condition  seems  to  get 
worse,  the  more  treatment  he  has,  and  is  especially  aggravated  if  too  strong  solutions 
are  used,  the  chances  are  that  the  chronic  urethritis  is  now  due  to  a  secondary 
infection. 

One  must  next  ascertain  that  there  is  no  active  prostatitis,  and  no  stricture 
of  the  urethra. 

The  patient  should  then  be  asked  if  the  morning  drop,  or  the  early  discharge, 
are  more  than  is  just  sufficient  to  stick  the  lips  of  the  meatal  orifice  together,  and 
whether  the  threads  in  the  urine  are  decreased  or  increased  in  the  morning  following 
a  sexual  connection,  a  nocturnal  emission,  or  the  taking  of  alcohol. 

All  three  are  almost  certain  to  aggravate  the  condition,  if  gonococci  are  still 
present.  The  first  two  may  improve  the  condition,  if  the  inflammation  is  due  to 
a  secondary  infection,  and  the  taking  of  alcohol  may  make  little  or  no  difference. 

The  patient  should  then  be  given  a  big  provocative  injection  of  a  potent 
non-sensitised  gonococcal  vaccine.  If  the  condition  during  the  first  forty-eight  hours 
after  the  injection  is  either  improved  or  aggravated,  gonococci  are  still  present. 
If  the  condition  remains  in  statu  quo  ante,  the  infiammation  is  more  probably  due 
to  a  secondary  infection. 

It  is  practically  useless  making  a  microscopic  examination  of  the  discharge 
or  threads,  because,  if  gonococci  are  present,  they  will  not  be  in  the  discharge  or 
threads,  but  only  in  the  sub-epithelial  tissue.  In  all  cases,  within  a  few  days  of  the 
infection,  a  microscopic  examination  of  the  discharge  reveals  myriads  of  other 
organisms.  The  presence  of  polymorphonuclears  does  not  assist  one  at  all  in 
making  a  diagnosis.  It  is  most  important  to  bear  in  mind  the  possibility  of  a 
secondary  infection,  since  it  is  usually  caused  by  inflammation  produced  by  too 
much  instrumentation  and  too  strong  antiseptic  solutions  ;  therefore,  any  treat- 
ment which  increases  this  inflammation  will  favour  the  invasion  of  the  sub- 
epithelial tissue  by  the  secondary  infection. 

A  urethritis  due  to  a  secondary  infection  is  not,  as  a  rule,  infectious. 

The  secondary  infection  is  usually  due  to  diphtheroids,  streptococci,  and 
staphylococci. 

The  presence   of  a  secondary   infection   can  be  positively  ascertained  by   a 


382  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   GONORRHOEA. 

provocative  injection  of  an  autogenous  vaccine,  made  from  the  organisms  cultured 
from  the  expressed  prostatic  secretion. 

A  urethritis  due  to  a  secondary  infection  is  best  left  alone,  so  far  as  local 
treatment  is  concerned,  and  recourse  had  only  to  injections  of  gonoccal  phylacogen. 

Treatment. 

Prophylaxis. — Malthusian    appliances,    washing    with    soap     and    water,    and 
micturating  immediately  after  coitus  are  useful.     On  the  Continent,  the  application 
of  antiseptics  to  the  urethra  is  practised,  generally  in  the  form  of  a  protargol  bougie  • 
or  injection. 

Treatinent  of  acute  urethritis  may  be  considered  under  three  heads  : — • 

1.  Hygienic. — First  of  all  rest,  both  to  the  part — by  wearing  a  suspensory 
bandage — and  to  the  person.  Bed  is  seldom  necessary,  but  active  exercise  must  be 
forbidden.  Alcohol  must  be  avoided,  and  milk  and  water  substituted.  If  the 
patient  has  beenusedtomuch  alcohol,  it  is  unwise  to  knock  it  off  suddenly,  but  one 
should  gradually  get  hmi  accustomed  to  further  dilution  with  water.  No  hot 
foods  and  condiments — mustard,  pepper,  sauces — must  be  taken.  The  diet 
should  be  as  free  of  meat  as  possible,  and  tasty  articles  of  food,  as  savouries,  hors 
ffoeumes,  shell  fish,  celery,  asparagus,  etc.,  should  be  avoided.  The  most 
important  matter  of  all  is  to  see  that  the  bowels  are  well  regulated. 

2.  Symptomatic. — Pain  can  generally  be  diminished  by  diluting  the  urine,  by 
giving  more  milk  and  water  ;  barley  water  is  excellent.  Decreasing  the  acidity  of 
urine  by  drinking  lime  water  often  afiords  relief.  For  the  acute  pain  caused  by 
spasm  of  the  compressor  urethrae  muscle,  nothing  is  better  than  a  warm  hip  bath, 
since  this  often  relieves  the  retention.  If  narcotics  be  required,  use  suppositories  of 
belladonna  or  opium.  To  prevent  erections,  the  bromides  are  useful.  In  haematuria, 
ergot  or  liq.  ferri  2)erchlor.  should  be  given  internally,  with  morphia  subcutane- 
ously,  which,  by  stopping  spasm,  acts  as  a  styptic. 

3.  Local. — Treatment  aims  at  the  destruction  of  the  coccus.  Two  routes  have 
been  tried  :  giving,  by  mouth,  such  drugs  as  are  excreted  through  the  urethra,  and 
direct  application  of  drugs  to  the  urethra  itself.  The  drugs  usually  given  internally 
are  resins  and  balsams,  such  as  cubebs,  copaiba,  turpentine,  and  sandal  wood  oil.  Of 
these,  sandal  wood  oil  is  the  best,  but  all  of  them  have  the  disadvantage  of  upsetting 
digestion  and  causing  rashes.  To  get  over  these  defects,  sandal  wood  oil  has  been 
put  up  in  capsules  {saiwesses),  the  membrane  of  which  is  not  digested  until  the 
pancreatic  juice  is  reached,  so  that  no  oil  gets  loose  in  the  stomach,  eructation  and 
vomiting  being  thus  avoided.  Balsams,  if  they  irritate  the  kidneys,  must  be 
avoided  when  there   is  any  suspicion  of   nephritis.     Sodium   salicylate   is  always 


UNCOMPLICATED   GONORRHOEA.  383 

a  useful  adjunct.     The  ianumerable  patent  drugs,  gonorrhol,  gonosan,  salosantal, 
etc.,  have  no  advantage  over  those  already  mentioned. 

For  direct  application  to  the  urethra,  two  groups  of  drugs  have  to  be  con- 
sidered :  the  pure  antiseptics,  like  potassium  permanganate,  protargo!  and  hegonon  ; 
and  the  antiseptic  astringents,  zinc  permanganate,  silver  nitrate,  argentamin,  and 
ichthargan.  Pure  antiseptics  should  be  used  in  the  early,  astringents  in  the  later 
stages  of  the  disease. 

Injection  should  not  be  commenced  so  long  as  there  is  any  swelling  of  the 
glans  penis,  oedema  of  the  prepuce,  phimosis,  dorsal  lymphangitis,  blood  in 
secretion,  or  painful  erections.  The  only  aim  at  this  stage — that  is  to  say,  if 
lavage  cannot  be  carried  out — should  be  to  allay  the  inflammation  by  such  simple 
means  as  lotio  plumbi  c  opio,  and,  internally,  hyoscyamus  and  sandal  wood  oil. 

When  inflammation  has  subsided,  pure  antiseptic  injections,  such  as  potassium 
permanganate  1:4000,  or  hegonon  0"1  per  cent.,  should  be  commenced.  The 
patient  should  inject  himself  three  times  in  every  twenty-four  hours,  at,  as  nearly 
as  possible,  eight-hour  intervals.  He  should,  by  holding  his  finger  over  the  meatus, 
retain  the  injection  about  five  minutes.  The  bulk  of  each  injection  should  be  about 
three  teaspoonfuls,  so  that  the  whole  of  the  diseased  membrane  shall  be  under  its 
influence  at  the  same  time.  The  exact  amount  should  always  be  given,  and  for  this 
purpose  a  12  c.c.  syringe,  with  a  conical  end,  over  which  the  orifice  of  the  urethra 
passes,  should  be  used.  Inject  very  slowly,  and  use  but  shght  pressure,  for,  if  injected 
too  quickly,  the  muscles  come  into  action,  and  the  whole  is  ejected. 

In  acute  posterior  urethritis,  no  local  treatment  must  be  started  until  the  sub- 
jective symptoms  have  disappeared.  Hip  baths,  sodium  salicylate,  and  sandal  wood 
oil  must  be  employed  until  subjective  symptoms  are  over,  then  lavage  should  be 
started  as  above  by  the  patient,  and  the  doctor,  when  the  symptoms  have  become 
subacute  or  chronic,  can  employ  either  Diday's  irrigation  or  instillation  by  Guyon's 
catheter.  The  difference  between  the  two  lies  in  the  fact  that,  in  the  former,  diluted 
solutions  in  large  quantity,  and,  in  the  latter,  concentrated  solutions  in  small 
quantity,  are  employed.  The  former  is  the  milder  and  better  to  start  with.  The 
patient  must  have  a  full  bladder,  but  should  pass  a  little  urine  to  clean  the  urethra. 
In  Diday's  method,  a  soft  catheter  is  passed  imtil  urine  just  begins  to  come  out  ; 
its  eye  must  then  be  in  the  bladder.  The  moment  urine  appears,  draw  the  cathetej' 
back,  say  half  an  inch,  until  no  more  comes  ;  its  eye  must  then  be  in  the  prostatic 
portion.  Then  inject  very  slowly  and  gently,  withdrawing  the  catheter  as  you 
inject.  The  solutions  most  used  are  protargol  1-2  per  cent.,  potassium  perman- 
ganate "02  per  cent.,  zinc  sulphocarbolate,  silver  nitrate  '2  per  cent.,  and  1  c.c. 
of  them  should  be  used  daily. 

)  2b 


38i  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   GONORRHOEA. 

In  acute  and  subacute  cases,  the  best  treatment  is  lavage,  carried  out  by  tlie 
patient  himself,  but  before  discussing  the  technique  of  lavage,  the  abortive  treatment 
must  be  considered.  If  the  patient  can  be  put  under  treatment  within  twenty-four 
hours  of  his  first  noticing  a  discharge,  which  is  usually  on  the  third  day  of  his  infection, 
the  abortive  treatment  may  be  successful.  The  abortive  treatment  should  not  be 
attempted  after  this  time,  as  it  may  make  the  patient  worse,  and  on  no  account 
should  it  be  tried  if  the  subjective  symptoms  are  at  all  severe. 

The  abortive  treatment  as  usually  employed,  should  not  be  continued  for  more 
than  three  days,  and,  if  it  has  been  successful,  no  gonococci  should  be  found  in  smears 
of  the  secretion  examined  at  the  end  of  the  third  day. 

Three  drugs  are  commonly  used — hegonon,  protargol,  and  argyrol.  They  are 
employed  in  solution,  and  injected  into  the  urethra  by  a  syringe,  in  the  following 
strengths,  respectively,  3  per  cent.,  5  per  cent.,  25  per  cent.,  or  the  anterior  part 
of  the  urethra  is  washed  out  with  solutions  of  a  weaker  strength,  1  per  cent.,  1  per 
cent.,  5  per  cent.  AVhen  the  fluid  is  inserted  by  means  of  a  syringe  or  by  lavage, 
it  should  be  done  twice  a  day,  and,  after  each  application,  it  is  a  good  plan  to  wash  out 
the  urethra  with  a  3  per  cent,  solution  of  aluminium  acetate,  to  overcome  the 
hyperaemia  caused  by  such  strong  solutions,  and  partly  to  lessen  the  pain.  It  is 
very  seldom  that  the  abortive  treatment  is  successful,  and  it  is  always  very  painful, 
so  that  it  is  usually  very  difficult  to  get  the  patient  to  consent  to  having  the  treat- 
ment twice  a  day. 

Fortunately,  we  have  another  method  of  abortive  treatment,  which  is  not  only 
generally  successful,  but  also  it  is  painleiss  ;  and,  furthermore,  if  it  is  apphed  too  late, 
the  patient's  condition  will  not  be  aggravated  by  it.  Indeed,  whenever  it 
is  started,  although  it  will  not  abort  the  attack,  it  will  improve  the  local  condition. 
The  method,  which  originated  with  Ballenger,®  has  been  used  by  him  with  very  great 
success,  and  I  can  substantiate  what  he  has  said.  Ballenger's  method  is  called  the 
"  Sealing  In  "  abortive  treatment. 

A  5  per  cent,  solution  of  argyrol  is  sealed  into  the  anterior  part  of  the  urethra, 
once  daily,  for  five  days.  The  solution  is  sealed  in  with  non-contractile  collodion, 
and  for  at  least  four  hours  at  a  time.  The  technique  is  simple,  but,  unless  it  is  done 
exactly,  the  attempt  will  fail.  The  patient  first  empties  his  bladder,  the  penis  is  then 
well  cleaned  and  dried,  and  a  syringe  is  obtained  which  just  holds  20-25  minims, 
and  no  more.  This  quantity  of  a  5  per  cent,  solution  of  argyrol  is  injected,  the 
syringe  removed  quickly,  the  lips  of  the  meatus  are  closed  together,  wiped,  and 
then  brushed  over  with  collodion.  The  lips  of  the  meatus  should  be  kept  pressed 
together  until  the  collodion  has  dried.  The  usual  fault  is  to  inject  too  much  arygrol, 
and  the  collodion  will  not  hold  it  in.     Acetone  will  remove  the  collodion  when 


1 


UNCOMPLICATED    GONORRHOEA.  385 

required.  When  the  solution  is  allowed  to  escape,  the  patient  should  drink  freely 
of  lime  water  or  barley  water,  so  as  to  flush  out  the  kidneys  well,  and  to  overcome 
the  hyperaemia  caused  by  the  argyrol.  A  very  imjoortant  point  to  remember  is, 
that  the  argyrol  solution  must  be  freshly  prepared  each  day.  All  the  organic  pre- 
parations of  silver,  oxidise  very  quickly  in  solution,  and  the  more  they  arc  oxidised 
the  less  their  bactericidal  action. 

Another  point  which  medical  men  never  seem  to  realise  is,  that  great  care  has 
to  be  taken  in  making  up  the  solutions  of  these  organic  silver  salts.  The  measured 
quantity  of  water  should  be  first  obtained,  and  then  the  powder  or  powdered  tablet 
should  be  slowly  dissolved  by  degrees  in  it.  The  water  should  never  be  poured 
on  to  the  powder,  as  the  protein  which  many  of  these  preparations  contain  is 
immediately  precipitated,  and  none  of  the  silver  goes  into  solution. 

In  all  ordinary  cases  of  acute  anterior  urethritis,  and  in  those  cases  in 
which  the  abortive  treatment  has  failed,  the  patient  should  either  be  treated  by 
lavage  or  by  injections,  and  only  by  the  latter  when  the  former  cannot  be  under- 
taken. 

The  lavage  may  either  be  undertaken  by  the  doctor  or  by  the  patient ;  if  by 
the  latter,  the  following  is  the  best  procedure  :  A  glass  receptacle  holding  from 
a  pint  to  two  pints  is  hung  up  on  the  wall,  and  from  it  hangs  about  five  feet  of 
rubber  tubing,  to  the  end  of  which  a  single  or  a  two-way  cannula  is  attached.  The 
patient  lies  in  a  bath  of  warm  water  and  washes  out  his  urethra  twice  a  day,  night 
and  morning,  with  either  a  solution  of  potassium  permanganate,  the  colour  of  which 
is  not  deeper  than  that  of  ordinary  red  blotting  paper — i.e.,  1  :  10,000 — 1  : 4,000 — 
or  with  a  0"05  per  cent. — O'lO  per  cent.. solution  of  hegonon.  If  weak  antiseptic 
solutions  are  always  employed,  no  harm  whatever  will  result,  and  the  patient  will 
never  get  a  stricture.  A  patient  only  gets  a  stricture  if  he  is  not  treated  at  all,  or 
if  he  is  treated  with  too  strong  solutions.  The  fear  of  driving  the  discharge  back 
into  the  posterior  part  of  the  urethra,  and  of  setting  up  an  acute  prostato-urethritis 
and  epididymitis,  is  theory,  and  does  not  occur  in  practice. 

If  the  lavage  is  carried  out  as  just  mentioned,  and  is  continued  for  fourteen  clear 
days  after  the  patient  last  saw  anything  in  the  morning  urine  at  all,  in  a  very  large 
percentage  of  cases  the  patient  will  be  cured,  and  he  will  never  develop  a  posterior 
urethritis. 

If  the  lavage  is  undertaken  by  the  doctor,  there  is  a  danger  of  starting  the 
antiperistaltic  contractions  which  lead  to  epididymitis.  If  done  by  the  patient 
himself,  there  is  not  this  risk,  since  a  patient  is  unable  to  wash  out  the  whole  length 
of  the  urethra  until  he  has  lost  his  self-consciousness  and  the  compressor  urethrae 
ceases  to  contract  against  any  fluid  that  is  injected.     As  a  patient  does  not  become 

2  b2 


38(3  THE    BIOLOGY,    CLINICAL   ASPECT    AND   TREATMENT    OF   GONORRHOEA. 

au  fait  at  washing  out  his  own  urethra  until  he  has  been  at  it  for  ten  days  or 
a  fortnight,  and  if  he  does  not  commence  the  treatment  until  all  the  subjective 
symptoms  of  the  posterior  urethritis  have  vanished,  and  as,  moreover,  the  fluid  will 
only  reach  the  posterior  part  of  the  urethra  slowly  and  naturally  and  never  by 
force,  the  risk  of  starting  the  antiperistaltic  movements  is  nil. 

In  subacute  urethritis,  lavage  should  also  be  employed,  internal  medication 
should  be  persisted  in,  and  more  energetic  local  treatment  at  the  hands  of  the 
physician  may  be  undertaken. 

The  following  prescription  is  the  one  I  find  most  usefal  in  acute  and  subacute 
urethritis : — 

R  Pot.  citratis    . .         . .         . .  . .  . .  gr.  x 

Hexamethyl.  tetram.  . .  . .  . .  gr  x 

Tinct.  hyoscyam.       . .         . .  . .  . .  3  ss. 

Spir.  chlorof.  . .         . .         . .  . .  . .  ill  xv 

Infus.  scoparii  . .         . .  . .  ad  5  ss. 

M.  f.  mist. 

S.  ,^  ss.  ex  aq.  sod.  efEervesc.  3  ii  ter.  p.c. 

If  the  patient  has  much  pain,  the  addition  of  sodium  salicylate  is  advisable, 
and  if  there  is  any  tendency  to  the  formation  of  a  narrowing  of  the  urethra,  potassium 
iodide  should  be  added  in  increasing  doses.  If  the  patient  can  endure  high  doses 
of  potassium  iodide,  it  is  quite  a  good  plan  to  syiinge  or  wash  out  the  urethra  with 
hydrogen  peroxide.  The  idea  is  that  the  HgOg  hberates  the  iodine  from  the  salt, 
and  allows  the  element  to  exert  its  powerful  antiseptic  action  locally.  More  satis- 
factory results  are  obtained  by  this  method  than  by  washing  out  the  urethra  with 
a  weak  solution  of  the  tincture,  or  by  injecting  colloidal  iodine. 

In  all  subacute  cases,  it  must  be  ascertained  whether  the  jjatient  has  a  narrowing 
of  the  urethra  or  not.  If  he  has,  Kollmann's  dilator  should  be  used  for  stretching 
it,  and  the  urethra  should  be  well  washed  out  through  the  instrument,  with  collosol 
argentum  or  with  a  0"5  per  cent,  solution  of  silver  nitrate. 

If  there  is  no  narrowing,  lavage  done  by  the  patient  himself  is  usually  sufficient, 
but,  if  the  posterior  part  of  the  urethra  is  involved,  an  Ultzmann's  catheter  should 
be  passed  every  other  daj',  and  an  injection  of  collosol  argentum  given  through  it. 

In  chronic  urethritis,  the  prostate  is  usually  affected,  and  the  treatment  is 
discussed  in  Chapter  XXXIII. 

In  uncomplicated  chronic  urethritis,  there  is  usually  a  narrowing  of  the  urethra, 
or  a  stricture,  which  is  the  cause  of  the  trouble.  If  only  a  narrowing,  dilatation 
with  a  Kollmann's  dilator,  and  prescribing  the  same  treatment  as  that  mentioned 


UNCOMPLICATED    GONORRHOEA.  387 

in  the  subacute  stage,  will  usually  produce  the  desired  result.  If  there  is  a  stricture, 
it  must  naturally  be  attended  to.  If  the  chronic  urethritis  is  due  to  a  secondary 
infection,  mercurial  preparations  are  more  efficacious  than  silver  ones  for  washing 
out  the  urethra. 

'  Neisser  (1879),  "  Zentralbl.  f.  d.  mod.  Wissensohaft,"  xvii,  497. 

-  Pappenheim  (1903),  "  Mon.  f.  prakl.  Derm.,"  xxxvi,  361. 

'  Leszozyiiski  (1904),  "  Arch.  f.  Derm.  u.  Syph.,"  Ixxi,  409. 

*  Czaplewski  (1896),  "  Hygien.  Rumlschau,"  vi,  1029. 

^  Ballenger  (1914),  "  Genito-Urinary  Dis.  and  Syphilis."     Butterworth  &  Co.      Loudon. 


CHAPTER  XXXIII. 

COMPLICATIONS    OF    URETHRITIS   GONORRHOICA,    DUE   TO   DIRECT 
EXTENSION  OF  THE   ORGANISM. 

COWPERITIS   GONORRHOICA. 

The  ducts  of  Cowper's  glands  open  into  the  penile  portion  of  the 
urethra,  hence  an  extension  of  the  organisms  into  these  glands  takes  origin 
from  an  anterior  urethritis.  Under  ordinary  circumstances,  Co^rper's  glands 
cannot  be  felt,  and  even  when  they  become  enlarged  they  are  missed,  unless  the 
observer  knows  exactly  how  to  locate  them.  The  forefinger  of  one  hand  is  inserted 
•per  rectum,  and  the  thumb  of  the  same  hand  is  pressed  against  the  triangular  ligament. 
The  forefinger  feels  for  the  region  of  the  symphysis,  i.e.,  for  the  middle  line,  and  then 
gradually  works  outwards  on  either  side,  remembering  always  to  keep  pressing 
anteriorly,  and,  in  the  lateral  course,  the  gland  will  be  felt  between  the  forefinger 
and  the  thumb.  In  my  experience,  abscess  formation  in  Cowper's  glands  is  more 
common  than  in  any  of  the  other  organs  affected  by  the  gonococcus.  Acute  inflam- 
matory Cowperitis  is  not  at  all  uncommon,  but  chronic  Cowperitis  is  relatively  rare. 

The  subjective  symptoms  of  Cowperitis  are  the  same  as  those  experienced  in 
inflammation  of  the  bulb,  and  they  are,  moreover,  characteristic.  The  first  thing 
a  patient  complains  of  is  pain  in  the  perineum,  but  the  pain  is  felt  only  in  the  acts 
of  sitting  down  and  getting  up.  Later  the  pain  becomes  more  acute,  and  extends 
to  the  rectum,  scrotum,  and  inner  surfaces  of  the  thighs.  Most  of  the  cases  of  acute 
Cowperitis  with  abscess  formation  which  I  have  seen,  have  burst  spontaneously 
in  the  perineum.  Owing  to  the  proximity  of  the  abscess  cavity  to  the  rectum, 
rectal  gonorrhoea  may  complicate  the  case,  but,  generally  speaking,  abscesses  in 
Cowper's  glands  heal  very  quickly,  and  without  any  compHcation.  The  abscess 
may  also  burst  into  the  urethra,  and  may,  in  the  process  of  heaUng,  lead  to  a  urethral 
strictiu'e. 

I  have  seen  two  cases  in  which  a  urinar)^  fistula  followed,  and  in  one  of  these 
the  patient  had  extravasation  of  urine.  Unless  the  patient  comes  up  for  treatment 
early,  and  unless  the  condition  heals  quickly,  a  fistula  is  very  liable  to  result. 


COMPLICATIONS   OF   GONORRHOEA    BY    DIRECT   EXTENSION.  389 

Urinary  fistulae,  following  Cowperitis,  do  not,  as  a  rule,  close  spontaneously,  so  it  is 
usually  necessary  to  dissect  out  both  the  fistula  and  the  gland.  Retention  cysts 
may  follow  a  Cowperitis,  in  the  same  way  as  a  labial  cyst  may  follow  a  Bartho- 
linitis.    In  both  cases,  the  only  means  of  curing  the  condition  is  extirpation. 

The  treatment  of  ordinary  Cowperitis  rests  in  local  applications  of  cold,  in  not 
incising  an  abscess  until  it  points,  and  in  treating  the  urethral  condition  as  if  a 
Cowperitis  did  not  exist. 

Folliculitis,  Perifolliculitis  and  Cavernitis  Gonorrhoica. 

A  folliculitis  is  very  common.  It  is  probably  partly  responsible  for  the 
chronicity  of  the  disease,  and  it  arises  from  an  infection  of  the  Littre's  glands  in  the 
mucous  membrane  of  the  urethra.  A  plain  folliculitis  is  indistinguishable  from  a 
plain  urethritis,  and  the  only  way  in  which  to  tell  whether  the  glands  are  infected 
or  not,  is  to  examine  the  urethra  endoscopically,  or  to  adopt  the  following  pro- 
cedure :  The  urethra  is  first  well  washed  out,  then  a  hougie-d-houle  is  passed,  and 
the  urethra  massaged  from  the  outside  over  it.  This  presses  out  the  secretion  from 
the  follicles,  which  sticks  to  the  bougie,  and  then  the  secretion  can  be  examined 
later  for  gonococci.  Fibrous  tissue  formation  is  common  in  all  gonococcal  lesions, 
especiall}'  in  those  lesions  which  do  not  suppurate.  As  suppuration  in  the  follicles 
leads  to  a  perifolliculitis,  when  reference  is  made  to  folliculitis  proper,  it  may  be 
assumed  at  once  that  the  lesion  or  lesions  are  never  suppurative.  This  being  the 
case,  fibrous  tissue  formation  is  a  common  sequence.  A  fibrotic  folliculitis  may 
either  lead  to  the  formation  of  hard  nodules,  or  even  to  a  stricture.  This  is  probably 
the  pathology  of  the  narrowing  or  narrowings,  as  there  are  often  two  or  even  three 
to  be  met  with  right  in  the  fore  part  of  the  urethra,  after  a  chronic  attack  of  gonor- 
rhoea. The  fossa  navicularis  is  a  favourite  site  for  folliculitis.  This  being  so,  it 
will  follow  that  perifolliculitis  wUl  frequently  have  its  origin  here. 

A  perifolliculitis  arising  from  the  fossa  navicularis  first  appears  as  a  hard 
swelling  on  the  under  surface  of  the  penis.  The  swelling  at  this  stage  is  not  par- 
ticularly painful  to  the  touch,  nor  markedly  inflammatory ;  hence  the  diagnosis 
of  intraurethral  chancre  is  often  made.  Such  a  mistake  in  diagnosis  need  not 
arise,  if  the  reader  will  bear  in  mind  that  almost  all  intraurethral  chancres  can  be 
seen  at  the  urethral  orifice,  and  that  one  part  of  the  chancre  has  usually  eroded  a 
portion  of  the  glans  penis.  Further,  micturition  is  very  painful  in  cases  of  peri- 
folhcuHtis.  The  swelhng  may  bulge  in  the  middle  fine,  and  may  either  burst  or 
spontaneously  disappear,  or  it  may  point  to  one,  or  more  often  to  both,  sides  of  the 
froenum  in  the  corona.  If  the  abscess  bursts  on  one  or  both  sides  of  the  foenum, 
pus  is  exuded  for  a  few  days,  and  then  the  opening  closes,  and   the   swelling 


390  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   GONORRHOEA. 

spontaneously  disappears.  Occasionally  a  penile  fistula  results.  In  my  experience, 
i  t  is  wisest  to  leave  these  fistulae  alone,  as  I  have  seldom  met  with  a  case  in  which 
they  did  not  ultimately  close  of  their  own  accord,  and  it  is  a  difficult  and  painful 
operation  to  close  such  a  big  opening  by  electrolysis.  A  perifolliculitis  may  burst 
anyTvhere  along  tbe  raphe  of  the  penis ;  it  may  also  point  laterally,  or  even  on  the 
dorsum  of  the  penis.  The  region  of  the  bulb  is  a  very  common  situation 
for  an  abscess. 

Treatment  by  rest  and  cold  applications,  or  by  painting  on  ichthyol,  will  often 
cause  these  abscesses  to  abort.  If  not,  they  should  be  allowed  to  point,  and  should 
then  be  incised  at  the  apex,  or  allowed  to  burst.  If  left  alone,  a  penile  fistula  prac- 
tically never  results,  except  when  the  abscess  arises  from  the  bulb,  and  even  then 
it  soon  closes.  In  most  of  the  cases,  a  folliculitis  does  not  become  a  perifolliculitis 
until  the  urethral  opening  of  the  fonuer  becomes  blocked.  The  more  the  abscess 
advances  to  the  skin,  the  thicker  the  fibrous  tissue  wall  it  leaves  behind  it.  There- 
fore, under  ordinary  circumstances,  a  penile  fistula  is  rare.  If  the  abscess  be  incised 
before  it  points,  or  if  too  big  an  incision  be  made,  a  false  passage  may  easily  be 
produced,  and  a  penile  fistula  is  very  apt  to  follow.  When  penile  fistulae  arise 
from  too  energetic  operative  treatment,  they  are  extremely  difficult  to  close,  while 
those  which  arise  from  Nature's  cure  heal  quickly,  therefore  no  harm  is  done  in 
letting  a  perifolliculitis  burst  of  its  own  accord. 

It  is  very  seldom  that  a  perifolliculitis  bursts  into  the  urethra. 

A  perifolliculitis  may  become  a  cavernitis,  that  is,  the  gonococci  may  spread 
peripherally  into  the  corpus  cavernosum.  All  that  results  may  be  a  dense  fibrous 
nodule  or  band,  which  may  be  so  bad  as  to  render  erection  almost  impossible,  in 
any  case  acutely  painful.  A  cavernitis,  on  the  other  hand,  may  be  suppurative, 
and  may  lead  at  first  to  a  perpetual  erection.  Some  of  these  cases  end  fatally  from 
pyaemia  ;  but,  as  a  rule,  they  resolve,  and,  owing  to  the  amount  of  fibrous  tissue 
formed,  and  to  the  contraction  of  the  same,  sexual  connection  is  for  ever  made  a 
difficult  and  usually  an  unpleasant  proceeding. 

Something  can  be  done  in  these  cases  by  prescribing  large  doses  of  potassium 
iodide  internally,  and  by  rubbing  in  iodex  ointment  externally.  Thiosinamine  or 
fibrolysin  has  been  strongly  recommended,  but  I  can  only  say  that  I  have  never 
seen  it  do  any  good. 

In  cases  of  folliculitis,  the  urethra  should  be  stretched  with  a  Kollmann's 
dilator,  and  well  washed  out  with  some  antiseptic.  Treating  each  follicle  by 
cauterisation  through  an  urethroscope  is  usually'  futile. 

The  name  periurethritis  is  often  given  to  the  three  conditions  which  have  just 
been  discussed,  and  this  must  not  be  confounded  with  the  term  paraurethritis. 


J 


complications  of  gonorrhoea  by  direct  extension.  391 

Paraurethritis. 

This  is  an  inflammation  of  either  accessory  nrethrae  or  canals  which 
branch  from  the  urethra,  and  it  is  usually  produced  by  the  gonococcus.  These 
canals  may  be  single  or  multiple,  they  may  open  externally  anywhere  along  the 
median  raphe  of  the  penis,  or  in  the  glans  penis  on  either  side  of  the  meatal  orifice. 
The  meatal  paraurethral  canals  may  open  in  the  meatus  itself.  The  point  is  not 
settled  whether  these  canals  are  always  congenital,  or  whether  they  are  sometimes 
produced  during  the  course  of  the  gonorrhoea.  They  vary  very  much  in  length, 
but  are  usually  about  2  centimetres  long.  Meatal  paraurethritis  is  a  frequent  cause 
of  recurrent  gonorrhoea,  reinfection,  and  infection. 

Any  pressure  from  behind  forces  the  discharge  out  of  the  canals,  and  the 
discharge  is  usifally  full  of  gonococci.  It  is  most  necessary,  as  soon  as  the  acute 
stage  of  the  gonorrhoea  is  over,  to  close  these  canals  as  soon  as  possible. "  Closure 
is  best  effected  by  electrolysis.  A  very  convenient  apparatus  is  Morton's  switch- 
board. To  the  negative  pole  is  attached  a  needle  holder,  containing  a  platinum 
needle,  or  a  fine  piece  of  platinum  wire.  The  needle  or  wire  is  then  passed  down  the 
canal,  after  all  the  discharge  has  been  pressed  out.  A  large  pad  is  attached  to  the 
positive  pole,  and  is  placed  under  one  of  the  buttocks.  A  current  of  1  to  4  milli- 
amperes  is  then  run  through  for  1  to  2  minutes.  More  than  one  application  may  be 
necessary.  If  several  applications  fail  to  close  the  canal,  it  will  mean  that  the 
needle  has  not  passed  down  it.  It  is  often  impossible  to  guide  the  needle  down  the 
lumen  of  the  canal,  in  which  case  the  canal  can  be  attacked  from  the  side,  in  its 
centre,  instead  of  through  its  opening.  Those  canals  along  the  median  raphe  of  the 
penis  are  especially  difficult  to  treat,  so  that  it  may  be  necessary  to  dissect  them 
out. 

Prostatitis. 

There  are  two  ways  of  examining  a  prostate  to  see  if  it  is  diseased — 
(a)  palpation  -per  rectum  ;  (6)  microscopic  examination  of  expressed  secretion.  In 
palpating  the  prostate  gland,  it  must  be  remembered  that  a  great  variation  normally 
exists  in  the  relative  sizes  of  the  two  lobes.  If  the  gland  is  enormously  enlarged, 
painful,  and  the  two  lobes  cannot  be  differentiated,  the  patient,  if  under  50  years  of 
age,  has  a  prostatic  abscess.  With  the  exception  of  the  increase  in  size,  due  to  an 
abscess,  it  is  better  to  discountenance  the  size,  and  to  pay  attention  to  the  con- 
sistency and  the  state  of  the  surface. 

In  most  cases  of  gonococcal  prostatitis,  only  one  portion  of  one  lobe  is  affected, 
or  several  distinct  portions  of  one  or  both  lobes  may  be  involved. 

The  affected  area  is,first  swollen,  painful,  and  soft ;  but,  as  the  condition  becomes 


392  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   GONORRHOEA. 

chronic,  and  fibrous  tissue  takes  the  place  of  the  celhilar  infiltration,  the  area 
becomes  hard,  and  eventually  indented,  owing  to  the  drawing  in  of  the  surface  by  the 
contraction  of  the  fibrous  tissue.  Consequently,  the  mere  examination  of  the 
surface  of  both  lobes  will  tell  the  observer  at  once  whether  the  gland  has  been 
affected  or  no.  Unevenness  of  the  surface,  or  irregularity  in  the  consistence  of  the 
different  areas,  signify  an  active  or  a  healed  gonococcal  infection.  One  can  only 
be  certain  whether  the  prostatitis  is  active  or  healed  by  making  a  microscopic 
examination  of  the  expressed  secretion.  Experience,  gained  by  the  palpation  of 
several  hundreds  of  cases,  will  usually  enable  a  trained  observer  to  say  at  once 
whether  the  condition  is  active  or  healed.  If  the  surface  or  the  consistence  of  the 
prostate  alters  on  massaging  the  gland,  it  denotes  active  trouble,  as  the  alteration 
is  due  to  pressing  out  the  cellular  debris  from  one  of  the  soft  and  swollen  areas. 
A  lobe  which  is  shrunken  and  uneven  on  the  surface,  due  to  the  contraction  of  fibrous 
bands  in  various  parts,  is  usually  indicative  of  a  healed  condition. 

Gonococci  should  be  looked  for  when  a  microscopic  examination  is  being 
undertaken,  and,  if  none  be  found,  attention  should  be  paid  to  the  number  and 
nature  of  the  leucocytes  present.  The  presence  of  polymorphonuclear  leucocytes 
alone  does  not  necessarily  signify  an  active  gonococcal  infection,  because  soon  after 
gonococci  reach  the  prostate  a  secondary  infection  follows  in  their  wake,  and  a 
secondary  infection  may  persist,  and  so  give  rise  to  the  production  of  polymorpho- 
nuclear leucocytes,  long  after  all  gonococci  have  disappeared.  If  there  are  a  great 
number  of  polymorphonuclear  leucocytes,  it  is  suggestive  of  an  active  gonococcal 
infection,  and  if  there  are  several  large  mononuclear  leucocytes  and  eosinophile 
cells,  it  is  practically  certain  that  there  are  gonococci  in  the  prostate  gland.  Trying 
to  grow  the  gonococcus  from  the  secretion  may  give  positive  evidence,  in  cases  where 
other  methods  have  failed. 

In  many  cases  of  prostatitis,  if  the  urine  be  carefully  examined,  in  the  last 
portion  passed  are  to  be  found  either  what  looks  like  a  granular  precipitate  or  bodies 
which  are  bigger,  but  not  quite  so  opaque.  The  size  and  density  depends  upon  the 
amount  of  mucin  present  in  the  particles.  The  particles  consist  of  pus  cells,  epi- 
thelial cells,  and  mucin,  and  they  are  pressed  out  of  the  acini  and  ducts  in  the  act  of 
expelling  the  last  few  drops  of  urine.  These  particles  m\ist  not  be  confused  with 
much  bigger  clear  bodies,  which  also  find  exit  with  the  last  few  drops  of  urine,  and 
which  arise  quite  independently  of  a  prostatitis.  These  bodies  are  about  the  size 
of,  and  look  very  much  like,  boiled  sago  grains.  They  often  go  by  the  name  of 
Lallemand-Trousseau  bodies,  and  they  come  from  the  vesiculae  seminales  and  con- 
sist merely  of  coagulated  mucin,  which  has  included  in  its  meshes  a  few  epithelial 
cells  and  leucocvtes. 


COMPLICATIONS    OF   GONORRHOEA    BY    DIRECT   EXTENSION.  393 

A  naked  eye  examination  of  the  threads  in  the  urine  will  often  give  a  clue  as 
to  whether  the  prostate  gland  is  implicated  or  not.  Long  threads  are  usually 
urethral  ;  if  they  are  dense  and  fall  quickly  to  the  bottom,  they  usually  consist 
of  myriads  of  leucocytes,  which  suggests  that  the  gonococcal  process  is  still  active. 
If  the  long  threads  float  for  some  time,  and  appear  more  transparent,  they  contain 
mostly  mucin,  which  indicates  that  the  treatment  is  being  overdone.  Punctate 
threads  usually  come  from  the  prostate,  and  their  presence  generally  means  that 
the  gonococcal  process  in  the  gland  is  active. 

Prostatic  Abscess. — The  prostate  often  swells  to  a  considerable  size,  before  giving 
rise  to  subjective  symptoms.  A  prostatic  abscess  may  even  burst  without  the 
patient  being  aware  that  he  had  had  an  abscess.  The  bursting  of  a  prostatic 
abscess  may  result  in  the  spontaneous  cure  of  the  disease. 

When  a  prostatic  abscess  gives  rise  to  subjective  symptoms,  those  usually 
complained  of  are  a  feeling  as  if  there  were  a  foreign  body  in  the  rectum,  acute 
pain  on  defaecation,  or  on  contraction  of  the  abdominal  muscles. 

Priapism  and  painful  pollutions  are  common.  These  prevent  the  patient 
from  sleeping.  Consequently  he  soon  begins  to  wear  a  haggard  expression,  and  looks 
very  ill.  Oddly  enough,  fever  is  far  from  being  a  constant  symptom.  Naturally, 
micturition  is  extremely  painful,  and  the  urine  may  be  quite  clear,  just  as  it  often 
is  in  the  early  stage  of  epidid3anitis. 

Many  cases  resolve  of  their  own  accord,  but  recurrences  are  very  liable  to  set 
in,  from  time  to  time. 

If  a  case  is  caught  early,  rest  in  bed,  the  internal  administration  of  urinary 
antiseptics,  and  the  intravenous  injections  of  vaccine  will  usually  quickly  bring 
about  resolution,  but  it  is  necessary  to  give  monthly  injections  of  vaccine  for  about 
a  year  afterwards,  to  prevent  a  recurrence. 

In  the  early  stage  of  practically  any  acute  inflammatory  condition,  the  applica- 
tion of  cold  may  be  very  beneficial. 

In  the  case  of  acute  parenchymatous  prostatitis,  cold  may  be  applied  to  the 
gland  by  inserting  a  psychrophore  into  the  rectum,  and  passing  a  continuous 
current  of  cold  water  through  it. 

Many  prostatic  abscesses  burst  spontaneously,  and  usually  into  the  urethra. 
The  majority  of  the  cases  heal  very  rapidly,  and  they  are  best  left  alone.  It  is  not 
wise  to  employ  any  local  treatment,  for  fear  of  breaking  down  part  of  the  abscess 
wall.  Breaking  down  the  abscess  wall  may  end  in  an  extravasation  of  urine, 
a  complication  which  is  extremely  rare  under  ordinary  circumstances.  Spontaneous 
rupture  into  the  rectum  may  occur.  Should  the  observer  have  reason  to  think 
that  the  abscess  is  going  to  burst  into  the  rectum,  he  should  forestall  it,  and  make 


39-i  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT    OF   GONORRHOEA. 

a  small  incision  at  the  place  where  the  abscess  is  pointing.  Cases  which  have  been 
treated  by  incision  run  a  better  course  than  those  in  which  the  abscess  bursts 
spontaneously — for  one  reason,  a  gonococcal  catarrhal  inflammation  of  the  rectal 
mucous  membrane  is  less  likely  to  supervene. 

A  rupture  of  a  prostatic  abscess  into  situations  other  than  those  just  men- 
tioned is  a  pathological  curiosity,  and  requires  no  special  mention. 

Chronic  Prostatitis. — A  chronic  inflammation  of  the  prostate  gland  is  the  lesion 
with  which  one  mostly  has  to  deal.  As  a  rule,  the  subjective  symptoms  are  nil. 
Chronic  prostatitis  undoubtedly  plays  a  rtle  in  the  aetiology  of  sexual  neurasthenia, 
but  this  is  a  subject  which  will  be  considered  by  itself  later.  The  objective  signs 
have  already  been  dealt  with,  but  nevertheless  a  point  should  be  emphasised,  i.e., 
that  in  the  two  glass  test,  should  the  second  glass  be  clear,  it  is  no  sure  proof  that 
the  prostate  is  not  affected.  In  many  cases  of  chronic  prostatitis,  the  inflammation 
is  so  slight  that  only  a  very  little  cellular  debris  finds  exit  into  the  urethra  during 
twenty-foar  hours.  The  little  that  is  in  the  urethra  may  be  washed  away  with 
the  first  few  drops  of  urine  passed,  and  this  would  leave  the  second  glass  clear. 
The  irrigation  test  in  such  a  case  does  not  help  one,  hence  it  is  necessary  to  palpate 
the  gland,  or  to  examine  its  expressed  secretion. 

An  increase  in  the  discharge,  or  in  the  number  of  threads,  or  a  decrease  of  the 
same  within  forty-eight  hours  of  a  provocative  injection  of  vaccine,  is  strongly 
suggestive  of  chronic  prostatitis,  since  on  plain  urethritis  vaccines  exert  little  influence. 

When  a  provocative  injection  of  vaccine  causes  a  nocturnal  emission  on  the 
same  night  or  the  next  night,  it  is  almost  certain  that  the  patient  has  a  chronic 
prostatitis. 

That  a  patient  develops,  on  the  one  hand,  an  increase  of  discharge  after  a 
provocative  injection  of  vaccine,  and,  on  the  other  hand,  a  decrease,  is  entirely 
due  to  the  state  in  which  the  antibody  was  when  the  injection  was  given.  If  the 
antibody  was  stale,  it  will  be  destroyed  when  a  vaccine  is  given,  and  therefore  the 
discharge  will  be  increased  ;  while  if  the  antibody  is  fresh,  the  vaccine  will 
stimulate  it,  and  therefore  the  discharge  will  be  decreased. 

In  the  cases  which  have  subjective  symptoms,  the  following  are  those  of  which 
the  patient  most  frequently  complains  : — Pain  in  the  rectum,  perineum,  and  small 
of  the  back.  The  pain  may  radiate  down  the  groins,  the  scrotum,  and  the  legs  ; 
it  is  often  aggravated  bj^  nocturnal  emissions  and  sexual  connection.  Itching 
sensations  around  the  anus  and  behind  the  scrotum  may  be  very  troublesome 
symptoms. 

Chronic  prostatitis  is  frequently  said  to  be  a  cause  of  sterility,  and  a  cause 
of  enlarged  prostate  in  later  life. 


COMPLICATIONS   OF   GONORRHOEA   BY    DIRECT   EXTENSION.  395 

111  most  cases  of  chronic  prostatitis,  oiJy  a  portion  of  one  lobe  is  affected, 
therefore  the  diminution  in  the  prostatic  secretion  is  negligible.  Even  if  the  normal 
secretion  is  reduced  to  practically  nil,  it  does  not  affect  the  vitality  of  the  sper- 
matozoa, and  there  is  no  proof  whatever  that  chronic  prostatitis  causes  sterility. 
Even  while  the  condition  is  stdl  active,  provided  there  are  no  gonococci  present, 
it  is  perfectly  safe  to  let  the  patient  marry.  In  my  opinion,  the  danger  of  infection 
is  very  much  over-estimated,  and,  if  the  case  has  been  well  treated,  the  risk  is 
practically  non-existent. 

As  to  whether  chronic  prostatitis  is  a  cause  of  prostatic  hypertrophy  is  merely 
a  matter  of  opinion,  as  no  proofs  can  be  adduced  for  or  against  the  suggestion.  I 
am  strongly  of  the  opinion  myself,  that  there  is  no  causal  relationship  between  the 
two  conditions. 

So  far  as  getting  rid  of  the  gonococci  from  cases  of  chronic  prostatitis  is 
concerned,  the  prognosis  is  good ;  but  as  regards  ridding  the  gland  of  leucocytes, 
the  prognosis  is  bad.  As  the  presence  of  leucocytes  means  nothing  more  than 
that  there  is  a  secondary  infection,  and  as  a  secondary  infection  is  harmless, 
and  as  it  may  give  rise  to  symptoms  indistinguishable  from  a  gonococcal  infection, 
it  is  most  important  to  differentiate  between  the  two  conditions. 

If  a  patient  has  been  well  treated,  and  if  neither  a  provocative  injection  of  a 
potent  vaccine,  nor  sexual  connection,  nor  a  nocturnal  emission,  nor  the  con- 
sumption of  alcohol,  alters  the  proportion  of  the  threads  in  the  urine,  I  think  the 
patient  may  be  informed  that  he  is  cured  and  fit  to  marry.  It  must  always  be 
remembered  that  the  mere  presence  of  threads  in  the  urine  does  not  mean  that  the 
patient  still  has  gonococci  lurking  about  somewhere.  Patients  who  have  undergone 
drastic  treatment  may  have  threads  for  the  rest  of  their  existence,  and  yet  be  quite 
cured  of  their  gonorrhoea.  Still  another  very  important  point  has  always  to  be 
borne  in  mind.  Patients  who  have  had  chronic  prostato-urethritis,  especiallv  if 
the  treatment  has  been  largely  instrumental,  and  if  strong  antiseptic  solutions 
have  been  injected,  are  very  liable  to  have  a  glycerine  discharge.  This  glycerine 
discharge  is  mucin,  which  continues  to  be  excreted  in  large  quantities  from  the 
mucous  membrane  of  the  ducts  and  acini  of  the  prostate  and  urethra  for  months, 
and  even  for  years  after  all  treatment  has  been  suspended. 

It  is  very  difficult  to  convince  neurasthenics  that  such  a  discharge  is  not 
gonococcal,  consequently  such  patients  run  from  one  doctor  to  another,  until  one 
has  been  found  who  will  treat  the  case.  As  the  mucin  discharge  is  due  to  irritation, 
it  will  naturally  follow  that  any  further  injections  will  only  tend  to  aggravate  the 
condition.  A  very  large  percentage  of  the  cases  I  see,  of  patients  who  have  had 
gonococcal  prostato-urethritis,  are  suffering  from  irritation  due  to  over  treatment. 


396  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OP   GONORRHOEA. 

I  think  it  is  highly  probable  that  more  cases  of  so-called  gleet  are  suffering  from 
over  than  from  under  treatment,  and  the  less  we  use  instruments,  and  the  weaker 
our  injection  solutions,  the  more  likelihood  there  is  of  curing  the  disease. 

The  treatment  in  chronic  prostato-uretliritis  is  quite  simple.  The  first  point 
that  must  be  ascertained  is,  whether  the  patient  has  a  stricture  or  narrowing  of  the 
urethra.  If  so,  then  this  must  be  dilated  before  any  special  treatment  is  begun. 
Tf  there  is  no  narrowing,  or  if  the  constricted  urethra  has  been  reduced  to  its  normal 
calibre,  the  patient  should  have  his  prostate  massaged  every  other  day  for  not 
longer  than  three  weeks.  The  prostate  is  massaged  with  the  forefinger  inserted 
fcr  rectum ;  the  finger  is  preferable  to  any  instrument.  An  Ultzmann's  syringe 
is  then  passed  down  the  urethra,  and  3  c.c.  of  either  collosol  argentum,  or  of  a  0  "5 
per  cent,  solution  of  silver  nitrate  is  injected. 

An  Ultzmann's  syringe  is  a  narrow  curved  metal  catheter,  which  only  reaches 
as  far  as  the  prostatic  poi-tion  of  the  urethra-,  and  it  has  a  fine  bore. 

The  patient  should  wash  himself  out  once  a  day  with  a  pint  of  a  1  :  2000 
solution  of  hegonon  or  albargin,  or  a  1  :  4000  solution  of  zinc  permanganate. 
Vaccines  should  be  given,  and  continued  monthly  for  six  months  after  the  patient 
has  been  cured.  The  best  and  simplest  means  of  telling  when  the  patient  is  cured 
is  the  behaviour  of  the  trouble  to  the  vaccines.  When  there  ceases  to  be  a  focal 
reaction,  i.e.,  when  the  discharge  or  threads  neither  increase  nor  decrease  within 
forty-eight  hours  of  the  last  injection,  it  is  probable  that  there  are  no  more  gonococci 
present.     The  daily  Ts-ash  out  should  be  continued  till  then. 

For  the  last  two  or  three  times  that  an  Ultzmann's  syringe  has  to  be  passed, 
it  is  a  good  plan  to  use  a  KoUmann's  posterior  dilator.  With  this  instrument,  one 
can  both  dilate  the  urethra,  and  inject  the  silver  salt  as  well. 

One  knows  only  too  well  how  common  recurrences  of  prostato-urethritis  are, 
but  it  is  not  so  well  known  that  a  fair  percentage  of  these  recurrences  are  not  due 
to  a  reawakening  of  a  gonococcus  colony,  but  are  merely  catarrhal  conditions. 
Observers  who  are  used  to  seeing  gonococcal  cases  will,  no  doubt,  have  noticed 
that  a  patient  will  never  get  a  recurrence  if  he  has  connection  with  his  wife,  but 
oiJy  if  he  has  connection  with  another  woman.  A  patient  who  has  had  a  gonococcal 
arthritis,  which  has  been  cured  for  years  past,  is  very  liable  to  get  a  slight  catarrhal 
synovitis  after  any  undue  exertion  of  that  joint,  or  changes  in  the  weather  may 
even  influence  it ;  but  such  cases  are  not  regarded  as  outbreaks  of  the  old  gonococcal 
infection — the  same  with  the  prostate. 

There  are  cases,  on  the  other  hand,  in  which  it  is  absolutely  impossible  to  lid 
the  prostate  of  gonococci,  and  a  cure  for  these  cases  is  yet  to  be  discovered.  I 
think  the  number  of  such  sad  instances  would  be  considerably  diminished.,  if  the 


COMPLICATIONS    OF   GONORRHOEA    BY    DIRECT   EXTENSION.  397 

rule  were  made  not  to  pass  more  instruments,  and  not  to  use  stronger  solutions  than 
were  absolutely  necessary,  in  all  cases  of  gonorrhoea.  1  am  certain  that  too  much 
and  too  drastic  treatment  are  the  curse  of  the  present-day  treatment  of  gonorrhoea. 

For  the  prostatorrhoea  which  may  follow  a  case  of  chronic  prostatitis,  prac- 
tically nothing  can  be  done.  The  most  important  thing  is  to  impress  upon  the 
patient  that  it  is  a  natural  sequence  of  the  treatment.  It  should  be  explained 
to  him  how  it  is  produced,  and  that  it  has  nothing  to  do  with  spermatorrhoea.  As 
a  rule  this  suffices,  and  the  patient  worries  no  more  about  it ;  but  if  he  is  still 
concerned,  the  secretion  of  mucin  can  be  diminished  a  little  by  using  a  urethral 
psychrophore  and  running  through  cold  water,  and  by  giving  belladonna  internally. 
Finger^  is  in  favour  of  ergotin  in  these  cases,  and  Sellei^  states  that  extractum 
Jiydrastis  liquidum  has  a  beneficial  action. 

The  treatment  of  chronic  prostatitis  is  long,  and  it  is  frequently  complicated 
by  sexual  neurasthenia,  so  that  the  physician  is  often  consulted  re  the  question  of 
having  sexual  connection.  In  the  present  day  of  faddists,  the  patient  may  stumble 
across  a  physician  who  may  be  led  by  his  moral  convictions  rather  than  by  the 
desire  to  do  the  best  for  his  patient. 

Provided  the  prostatic  discharge  is  gonococcal  free,  sexual  connection,  once  or 
twice  a  month,  often  has  a  very  beneficial  eft'ect  upon  a  case  of  prostato-urethritis, 
and  this  may  be  especially  noticeable  if  the  condition  is  further  complicated  by 
sexual  neurasthenia.  One  cannot  be  too  careful  in  the  treatment  of  a  neurasthenic. 
In  bad  cases,  a  sexual  neurasthenic  may  lose  all  sexual  power,  and  may  be  unable 
to  get  an  erection,  in  a  short  space  of  time.  Such  a  state  of  afl'airs  aggravates  his 
condition,  and  may  lead  to  suicide.  Allowing  the  patient  to  have  occasional  sexual 
connection  at  the  beginning  is  often  the  only  means  of  saving  him.  It  is  exactly 
the  same  with  an  alcoholic  and  with  a  patient  addicted  to  drugs.  Sudden  stoppage 
may  lead  to  disaster,  while  gradual  stoppage  may  result  in  one's  being  able  to  cure 
the  patient. 

Cystitis  Gonorrhoica. 

Considering  the  fact  that  the  urethra  and  the  bladder  are  continuous,  it 
might,  a  priori,  be  assumed  that  gonococcal  cystitis  would  be  as  common  as 
acute  posterior  urethritis.  Although  the  statement  has  been  copied  from  one 
textbook  to  the  other,  that  gonococcal  cystitis  is  a  common  complication  of 
gonorrhoea,  it  is  nevertheless  the  fact  that  cystitis  is  one  of  th«  complications 
most  rarely  to  be  met  with.  Another  reason  why  gonococcal  cystitis  is  said  to  be 
common,  is  due  to  the  fact  that  many  cases  of  acute  posterior  urethritis  are  ^^  rongly 


398 


THE   BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   GONORRHOEA. 


diagnosed  as  cases  of  cystitis.  The  mucous  membrane  of  the  bladder  must  be 
peculiarly  insensitive  to  the  gonococcus,  since,  in  all  cases  of  posterior  urethritis, 
pus,  containing  myriads  of  gonococci,  gains  entrance  to  the  bladder,  in  which 
organisms  may  remain  alive  for  hours.  The  bladder  mucous  membrane  appears 
to  be  not  only  insensitive  to  the  gonococcus,  but  to  most  other  bacilli,  as  evidenced 
by  the  rarity  of  cystitis  in  cases  of  bacilluria,  due  to  the  bacillus  coli,  etc. 

In  true  cases  of  gonococcal  cystitis,  gonococci  cannot  be  found  in  the  urine 
for  more  than  two  or  three  days,  as  they  quickly  give  place  to  a  secondary  infection, 
by  which  they  are  exterminated.  It  is  not  very  easy  to  distinguish  a  case  of 
gonococcal  cystitis  from  a  case  of  very  severe  posterior  urethritis,  but  in  the  former 
the  patient  almost  always  complains  of  a  very  dull  aching  pain  over  the  symphysis. 
Further,  however  frequent  be  the  act  of  micturition,  the  second  glass  test  in  cases 
of  cystitis  is  always  thick — indeed,  it  may  be  thicker  than  the  first,  and  it  always 
contains  more  gonococci.  Bleeding  at  the  end  of  micturition  is  common,  in  acute 
cases  of  posterior  urethritis.  In  the  case  of  cystitis,  all  the  urine  passed  is  blood- 
'  stained,  and  there  is  no  more  blood  in  the  last  portion  than  in  the  first. 

In  all  cases  of  cystitis,  the  patient  looks  extremely  ill,  has  fever,  and  sweats 
profusely.  So  long  as  the  cystitis  remains  gonococcal,  the  urine  is  acid  ;  when  the 
secondary  infection  supervenes,  the  urine  becomes  alkaline.  If,  instead  of  the 
two-glass  test,  three  glasses  be  used,  the  urine  passed  into  the  third  will  be  the 
thickest  in  cases  of  cystitis,  and  in  cases  of  posterior  urethritis  there  will  be  no 
difference  in  the  opacity  of  the  three. 

The  organism  which  most  frequently  takes  the  place  of  the  gonococcus  is  the 
bacillus  coli.  Every  case  of  cystitis  should  be  treated  as  quickly  as  possible,  since 
the  prognosis  of  true  gonococcal  cystitis  is  good,  but  the  moment  a  secondary 
infection  takes  its  place,  the  course  of  the  disease  may  be  very  long.  On  no  account 
should  an  instrument  be  passed,  as  it  is  certain  to  hasten  the  advent  of  the  secondary 
infection. 

The  patient  should  be  put  to  bed,  and  cold  compresses  applied  to  the  lower 
part  of  the  abdomen  and  perineum.  The  following  medicine  should  be  given 
internally  : — 

li  Sod.  salicyl gr.  x 

Hexameth.  tetramine    . .         . .         . .         gr.  x 

Pot.  citratis        gr.  x 

Tinct.  hyoscyam  . .         . .         . .         3  ss. 

Inf  us.  scoparii    . .  . .  . .  . .    ad  3  ss. 

M.  f.  mist. 

Cap.  3  ss.  ex  aq.  sodae  5  jj  ter  p.c. 


COMPLICATIONS   OF   GONORRHOEA    BY    DIRECT    EXTENSION.  399 

The  bladder  should  be  washed  out  twice  a  day  with  a  1  :  2000  solution  of 
hegonon,  from  the  tip  of  the  urethra  (Janet's  wash-out).  A  sensitised  vaccine 
should  be  injected  intravenously,  if  handy. 

Vesiculitis. 

Tiie  seminal  vesicles  are  not  very  easy  to  palpate.  When  an  examination 
is  being  undertaken,  the  knee  elbow  position  is  the  best,  and  the  bladder 
should  be  full.  Examination  of  the  secretion  is  often  as  necessary  as  mere 
palpation.  To  collect  the  seminal  secretion,  the  following  procedure  is  advised : 
The  patient  should  have  a  full  bladder,  the  prostate  is  then  massaged,  and,  if  the 
prostatic  secretion  shows  at  the  urethral  orifice,  the  bladder  should  be  not  quite 
emptied.  Then  the  seminal  vesicles  can  be  massaged,  and  the  secretion  from  them 
washed  out  with  the  remaining  fluid  in  the  bladder.  If,  after  massaging  the  pros- 
tate, the  prostatic  secretion  does  not  show  at  the  urethral  orifice,  the  chances  are 
that  it  has  passed  back  into  the  bladder.  When  such  is  the  case,  it  is,  of  course, 
necessary  to  empty  the  bladder  before  examining  the  vesiculae  seminales.  As  the 
expressed  seminal  secretion  usually  falls  back  into  the  bladder,  it  can  be  washed 
out  with  a  little  sterile  water. 

Spermatocystitis  gononhoica  occurs  more  frequently  than  is  supposed  to  be 
the  case,  but  the  subjective  symptoms  are  few,  and,  in  many  cases,  it  is  impossible 
to  palpate  the  seminal  vesicles,  consequently  they  are  not  often  examined.  The 
vesiculae  seminales  are  infected  via  the  ejaculatory  ducts.  Inflammation  without 
abscess  formation  is  the  usual  trouble,  an  abscess  of  the  seminal  vesicles  being 
comparatively  rare.  The  same  holds  good  in  the  case  of  the  prostate  and  the 
epididymis. 

I  once  had  a  case  of  spermatocystitic  abscess,  in  which  a  regular  bag  could  be 
felt  per  rectum,  overlapping  the  upper  pole  of  the  prostate,  and  it  emptied  itself 
of  its  own  accord  when  the  patient  assumed  the  knee  elbow  position.  Massage 
of  the  seminal  vesicles,  daily  washing  out,  and  vaccines,  resulted  in  a  complete  cure 
of  the  case. 

The  usual  subjective  symptoms  are  painful  micturition,  acute  pain  on  ejacula- 
tion of  semen,  and  peculiar  sensations  in  the  perineal  and  perianal  regions.  Sexual 
desire  is  frequently  stimulated,  and  the  patient  may  suffer  from  extended  erections, 
or  even  from  priapism.  If  the  ejaculatory  ducts  are  closed  by  the  inflammation, 
the  patient  is  unable  to  express  the  semen  during  sexual  connection,  with  the  result 
that  instead  of  having  an  orgasm,  he  experiences  the  most  excruciating  pains. 
The  pains  begin  in  the  perineum,  spread  to  the  rectum,  scrotum,  and  even  down 
the  legs.     The  type  of  sensation  described  is  absolutely  typical. 

2c 


■iOO  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   GONORRHOEA. 

A  microscopic  examination  of  the  seminal  secretion  should  be  undertaken, 
with  the  view  of  seeing  if  there  are  any  gonococci  and  pus  cells,  and  if  the  sper- 
matozoa are  destoyed  or  not. 

Chronic  spermatocystitis  may  give  rise  to  no  symptoms,  but  it  should  be 
remembered  that  it  is  a  very  frequent  cause  of  sexual  neurasthenia.  The  patient's 
sexual  desire  is  often  increased,  but  the  pleasure  derived  therefrom  is  often  nil, 
the  quantity  of  semen  may  be  very  small,  and  occasionally  blood-stained — all 
symptoms  which  are  very  liable  to  lead  to  sexual  neurasthenia,  or  to  aggravate  it, 
if  the  patient  is  already  suffering  from  it.  As  too  energetic  instrumentation  and 
the  use  of  too  strong  solutions  may  lead  to  prostatorrhoea,  so  may  they  lead  to 
spermatorrhoea,  and  the  occurrence  of  the  Lallemand-Trousseau  bodies  is,  in  my 
experience,  usually  a  sign  of  the  increased  secretion  which  emanates  from  mucous 
membranes,  both  after  a  chronic  inflammatory  lesion  has  been  got  rid  of,  and  when 
the  treatment  has  been  too  drastic.  In  very  acute  cases,  the  application  of  cold  per 
rectum  should  be  tried,  but  immediately  discontinued,  if  the  symptoms  show  signs 
of  being  aggravated.  Narcotics,  in  the  form  of  suppositories,  should  be  inserted 
per  rectum.  In  chronic  cases,  massage  of  the  vesiculae  seminales  should  be  under- 
taken, but  the  process  should  not  be  prolonged  nor  be  too  frequent — not  more  than 
once  every  other  day  for  about  twelve  times.  After  massage,  coUosol  argentum 
should  be  injected  into  the  posterior  part  of  the  urethra,  by  means  of  an  Ultzmann's 
syringe.  The  patient  should  wash  himself  out  daily  with  a  1  :  2000  solution  of 
hegonon,  and  vaccines  should  be  employed.  In  all  chronic  gonococcal  lesions, 
potassium  iodide  and  sodium  salicylate  should  be  given  internally,  and  in  the  case  of 
chronic  prostatitis  and  spermatocystitis,  iodex  suppositories  can  certainly  be  used 
with  advantage. 

Massage  of  the  seminal  vesicles,  plus  the  treatment  which  I  have  already 
outlined,  is  often  the  only  means  of  curing  a  case  of  spermatorrhoea  and  sexual 
neurasthenia,  but,  in  both  these  conditions,  success  sometimes  follows  the  cold 
water  treatment  by  means  of  the  urethral  psychrophore. 

Massage,  etc.,  will  usually  result  in  closed  ejaculatory  ducts  becoming  patent 
again,  but  this  is  not  always  the  case.  \\Tien  ordinary  treatment  appears  to  be 
unavailing,  it  is  advised  to  probe  the  ducts  via  a  urethroscope,  but  I  have  yet  to 
see  a  case  in  which  such  a  procedure  has  been  successful. 

Deferentitis. 

According  to  Oppenheim  and  Low,^  the  organisms  reach  the  epididymis 
by  means  of  an  antiperistaltic  movement  of  the  vas  deferens,  which  commences 
at  the  coUiculus  seminalis.     Although   the  condition  is  rare,  the  gonococci  may. 


COMPLICATIONS   OF   GONORRHOEA    BY    DIRECT    EXTENSION.  401 

on  their  passage  along  the  vas,  give  rise  to  a  true  deferentitis.  Deferentitis  rarely 
occurs  without  an  epididymitis,  while  an  epididymitis  without  a  deferentitis 
is  the  rule.  Therefore  the  symptoms  of  deferentitis  are  practically  the  same  as 
those  to  be  now  described,  under  the  heading  of  "  Epididymitis."  The  vas  can 
usually  be  felt  along  its  course,  as  the  cellular  tissue  around  it  is  usually  inflamed 
in  sympathy,  consequently,  one  is  really  dealing  with  a  funiculitis.  The  pain  in 
the  inguinal  region  is  very  severe,  and  it  usually  radiates  down  the  inner  side  of  the 
thigh. 

Epididymitis. 

Epididymitis  results  from  a  direct  extension  of  the  gonococci  from  the 
urethra.  Owing  to  the  stagnation  of  the  stream,  the  gonococci  settle  in  the 
caput  minor,  hence  it  is  usually  the  lower  pole  of  the  epididymis  which  is 
affected.  Owing  to  the  more  dependent  position  of  the  left  testicle,  the  epididymis 
on  this  side  is  more  frequently  affected  than  on  the  other.  Unwise  instrumentation 
in  the  acute  stage  of  urethritis,  and  massaging  a  prostate  gland  in  the  acute  or  sub- 
acute stages  of  prostatitis,  often  results  in  the  onset  of  an  epidid)'mitis.  Washing 
out  the  urethra  from  the  tip,  in  acute  cases  of  both  anterior  and  posterior  urethritis 
will  not  provoke  an  epididymitis,  unless  the  solutions  used  be  too  strong,  or  the 
pressure  at  which  they  are  injected  be  too  great.  By  far  the  greater  number  of 
cases  of  epididymitis  arise  in  those  individuals  who  have  been  treated  by  internal 
medicamentation  only. 

As  a  rule,  before  an  epididymitis  gives  rise  to  objective  symptoms,  the  patient 
complains  of  drawing  pains  in  the  inguinal  region,  and  of  neuralgic  pains  in  the 
testicle  and  upper  part  of  the  thigh  on  the  affected  side.  The  testicle  often  feels 
unusually  heavy.  If  the  patient  is  made  to  rest  at  once,  to  have  ice  or  cold  com- 
presses applied,  to  be  injected  with  a  sensitised  vaccine,  and  to  suspend  urethral 
treatment,  the  majority  of  cases,  if  diagnosed  thus  early,  never  develop  objective 
symptoms. 

As  a  rule,  it  is  the  objective  symptoms  which  compel  the  patient  to  seek  advice. 
Such  symptoms  are  usually  ushered  in  by  high  fever,  rigor,  etc.,  and  within  a  few 
hours  the  affected  testicle  is  about  three  or  four  times  its  natural  size.  The  skin 
of  the  scrotum  becomes  oedematous,  fluid  forms  in  the  sack,  and  the  inflammation, 
which  commences  at  the  caput  minor,  spreads  to  the  body  and  caput  major  of  the 
epididymis.  The  testis  itself  is  very  seldom  affected.  A  transient  peritonitis  is 
also  a  rare  complication. 

The  acute  inflammation  in  time  subsides,  and  leaves  a  hard  and  swollen  nodule 
in  the  lower  pole  of  the  epididymis.     Only  rarely  does  the  epididymis  become 

2c  2 


402  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   GONORRHOEA. 

adherent  to  the  skin.     When  this  happens,  there  is  always  an  abscess  in  the  epi- 
didymis, and,  in  the  majority  of  the  cases,  the  abscess  bursts  through  the  skin. 
Bursting  of  an  abscess  through  the  skin  usually  results  in  the  spontaneous  cure  of 
the  epididymitis. 

Owing  to  the  density  of  the  fibrous  tissue  which  forms  in  the  tail  of  the 
•epididymis,  and  which  may  be  sufficient  to  constrict  all  the  tubules,  it  is  necessary, 
especially  if  both  sides  are  affected,  to  put  the  patient  under  treatment  at  the 
earliest    possible    moment.     Dense    fibrous    tissue    formation,    following    bilateral 
epididymitis,  is  certain  to  cause  sterility.     The  patient  should  be  put  to  bed,  and 
ice  or  cold  evaporating  lotions  should  be  applied.     Personally  I  prefer  cold  to  hot 
applications,  but  the  former  are  more  difficult  to  manage.     Should  the  application 
of  cold  quickly  aggravate  the  symptoms,  it  means  that  the  inflammation  has  over- 
stepped that  stage  in  which  cold  applications  can  do  any  good.     Then  hot  fomenta- 
tions are  useful,  and  painting  the  organ  daily  with  ichthyol  is  a  good  substitute. 
Cold  will  often  abort  acute  iioflammation,  heat  never  will.       Heat  is  mainly  useful 
in  bringing  the  inflammation  to  a  head. 

Cold  applications  will  fail  in  their  pui'pose  if  they  are  allowed  to  get  warm 
and  clammy,  hence  they  are  difficult  to  use.     Cold  applications  which  become 
clammy,  quickly  lead  to  venous  congestion,  and  this  may  readily  cause  the  inflam- 
matory process  to  extend.     Ice  is  the  best  cold  application,  and,  failing  that,  an 
evaporating  lotion.     When  an  evaporating  lotion  is  used,  the  dressing  shoidd  be 
changed  several  times  a  day,  and  it  should  always  be  lightly  covered  over. 
The  following  is  a  good  evaporating  lotion  : — 

R  Plumbi  subacetat.         . .         . .         . .         gr-  x 

Liq.  amnion,  fort.  . .  . .  . .  m^  v 

Spir.  vini.  rect.  . .         . .         . .         5  j 

Sol.  alumin.  acetat.  3%  . .         . .    ad  5  j 

When  the  patient  gets  up,  a  suspensory  bandage  should  be  worn  until  he  has 
been  completely  cured  of  his  gonorrhoea.     While  in  bed,  it  is  a  good  plan  to  suspend 
the  testicles  by  a  broad  bandage  from  the  shoulders.     The  diet  should  be  light, 
and  the  following  medicine  should  be  taken  internally  : — 

H  Pot.  citratis        . .         . .         . .         . .         gr.  x 

Sod.  salicylatis  . .         . .         . .         . .         gr.  x 

Tinct.  hyoscyam.  . .  ...      . .         5  ss. 

Spir.  chloroformi  . .         . .         . .         ii).  xv 

Infus.  scoparii    . .         . .         . .         . .  ad  ,'5  ss. 

M.  f.  mist. 
S.  Cap.  ^  ss.  ex  aq.  sodae  effervesc.  J  ij  omn.  quartes  hores. 


COMPLICATIONS   OF   GONORRHOEA    BY    DIRECT   EXTENSION.  103 

If  the  pain  is  very  bad,  morphia  suppositories  should  be  used.  In  every  case, 
great  attention  should  be  paid  to  the  bowels,  and  sensitised  vaccines  should  be 
injected  intravenously  without  delay.  A  characteristic  of  all  gonococcal  foci  is 
that  they  recur,  even  after  they  have  been  apparently  cured,  and  gonococcal 
epididymitis  is  no  exception  to  this  rule;  therefore,  monthly  injections  of  a  potent 
vaccine  should  be  prescribed,  for  at  least  six  months  after  the  epididymitis  has 
vanished. 

Provided  the  urethra  is  washed  out  gently,  and  very  weak  solutions  are  used, 
there  is  no  reason  to  suspend  the  treatment  of  this  part.  If  both  testicles  are 
affected,  or  the  only  sound  one,  and  provided  the  case  is  seen  early  enough,  radical 
local  treatment  may  save  the  epididymis  from  becoming  injured  or  disorganised. 
Either  of  the  two  following  methods  of  treatment  may  be  employed  ;  the  first 
is  simpler  and  more  efficacious  : — 

1.  The  scrotum  is  taken  in  the  left  hand,  and  the  skin  is  made  taut  over  the 
affected  epididymis.  A  shai-p-pointed  bistoury  is  then  plunged  into  the  epi- 
didymis at  two  or  three  points,  parallel  to  the  tubules.  The  pain  is  momentary, 
and  the  relief  afforded  is  almost  instantaneous. 

2.  1-2  c.c.  of  electrargol  are  injected  into  the  epididymis.  The  epididymis 
reaches  almost  its  normal  size  in  1-3  days,  but,  as  a  rule,  a  second  injection  is 
necessary  to  produce  complete  resolution.  The  rapid  administration  of  sensitised 
vaccines  intravenously  has  practically  made  both  of  these  methods  superfluous. 

Ureteritis,  Pyelitis,  and  Pyelonephritis  Gonorrhoica. 

There  are  three  ways  in  which  the  urinary  tract  above  the  bladder  may  be 
involved  :  (a)  direct  extension  from  the  bladder  ;  (6)  via  the  blood  stream  ;  (c) 
via  the  lymphatic  stream.  Neither  ureteritis,  nor  pyelitis,  nor  pyelonephritis  are 
common  complications,  consequently  it  is  not  easy  to  say  by  which  route  the  infec- 
tion usually  reaches  these  structures.  If  ureteritis,  etc.,  follow  a  gonococcal  cystitis, 
the  chances  are  that  the  infection  has  spread  per  continuitafem ,  but  should  a 
pyelitis  or  a  pyelonephritis  occur  independently  of  a  cystitis,  presumably  the 
infection  is  a  blood  or  lymphatic  one.  That  the  gonococcus  can  reach  the  kidney 
by  the  blood  and  the  lymphatic  stream,  is  proved  by  the  cases  of  perinephritic 
abscesses  which  sometimes  follow  gonorrhoea.  Whether  a  perinephritic  abscess  is 
haemic  or  lymphatic  in  origin  it  is  impossible  to  say. 

Ureteritis  at  any  rate  is  due  to  a  direct  extension  of  the  gonococcus  from  the 
bladder.  Ureteritis  can  only  be  diagnosed  by  a  cystoscopic  examination  of  the 
bladder.     A  patient  suffering  from  pyelitis  or  pyelonephritis  is  always  extremely 


404  THE    BIOLOGY,    CLINICAL    ASPECT   AND    TREATMENT   OF   GONORRHOEA. 

ill,  the  complexion  is  white,  fever  is  constant,  and  there  is  nearly  always  profuse 
sweating.  There  is  pain  and  tenderness  over  the  kidney  region ;  the  pain  may 
run  down  to  the  penis  and  scrotum,  and  even  to  the  leg,  and  colic  attacks  may  be 
experienced,  as  if  the  patient  had  a  stone.  A  swelling  is  often  to  be  felt  in  the 
kidney  region,  and  there  is  usually  marked  polyuria,  and,  of  course,  pyuria.  Owing 
to  the  fact  that  there  is  cystitis  in  most  of  these  cases,  a  certain  diagnosis  cannot 
be  made,  except  by  catheterising  the  ureters,  a  procedure  one  does  not  care  to 
undertake  in  such  an  acute  condition.  A  diagnosis  may  sometimes  be  made 
between  cystitis  and  pyelitis,  by  comparing  the  quantity  of  pus  with  the  amount  of 
protein.  In  the  severest  cases  of  cystitis,  according  to  Rosenfeld,*  the  amount  of 
protein,  in  the  urine  which  has  been  allowed  to  settle  never  exceeds  0"15  per  cent.  ; 
while  the  protein,  in  cases  of  pyelitis,  in  which  the  urine  is  no  thicker  than  that 
from  cases  of  cystitis,  is  always  two  to  three  times  as  much. 

Finding  broken  up  red  blood  corpuscles  in  the  sediment  is  highly  suggestive 
of  pyelitis.  Great  attention  is  usually  paid  to  the  kind  of  epithelial  cell  found  in 
the  urinary  deposit,  but  it  is  very  easy  to  confuse  the  different  varieties. 

Gonorrhoea  may  cause  nephritis,  but.  as  a  rule,  parenchymatous  nephritis 
occurs  only  in  cases  suffering  from  gonococcal  endocarditis. 

Balsamic  nephritis  is  frecjuently  talked  about,  but  seldom  seen,  and  it  is  very 
doubtful  whether  albuminuria  often  follows  the  administration  of  sandal  wood 
oil,  copaiba,  etc.  Some  observers  are  of  the  opinion  that  a  gonococcal  cystitis  and 
pyelitis  open  the  door  for  a  tubercular  affection  of  these  organs,  in  the  same  way 
as  gonococcal  epididymitis  is  supposed  to  predispose  the  organ  to  an  infection  with 
the  tubercle  bacillus.  Tuberculosis  of  the  urinary  tract  is  so  common  in  patients 
who  have  never  had  gonorrhoea,  and  gonorrhoea  is  so  common  in  patients  who 
never  develop  tuberculosis,  that  it  is  quite  impossible  to  say  whether  gonorrhoea 
is  a  predisposing  factor  or  not.  The  treatment  of  these  complications  can  better 
be  studied  in  books  dealing  wath  general  medicine  and  surgery,  but  there  is  one 
point  which  may  be  mentioned  with  advantage  here,  a  point  which  I  learnt  in 
Finger's  clinic  in  Vienna.  It  is  the  administration  of  narcotics,  which  are  pre- 
scribed with  the  idea  of  checking  the  contractions  of  the  sphincter.  There  is  no 
doubt  that  frequent  and  constant  contractions  of  a  sphincter,  in  an  acute  inflam- 
matory condition  of  the  mucous  membrane  on  its  proximal  side,  is  very  apt  to  lead 
to  an  extension  of  the  inflammation  to  the  mucous  membrane  on  its  distal  side. 

Proctitis  Gonorrhoica. 

Gonococcal  inflammation  of  the  rectum  may  be  a  primary  lesion  or  a 
secondary    one,    due    to    an    extension    of   the   organisms   from   the    urogenital 


COMPLICATIONS    OF   GONORRHOEA    BV    DIRECT    EXTENSION.  405 

tract.  Owing  to  the  proximity  of  the  vagina  and  the  anus,  gonococcal  proctitis 
is  much  more  common  in  women  than  in  men.  Actual  figures  as  to  the 
frequency  of  the  rectal  complication  vary  enormously,  but  it  may  safely  be  said  that 
it  occurs  in  a  much  higher  percentage  of  cases  than  is  generally  thought  to  be  the 
case,  and  there  can  be  no  doubt  whatever  but  that  it  is  a  fi-equent  source  of  infec- 
tion to  a  second  party. 

The  symptoms  are  far  from  marked,  and  they  often  consist  of  Pruritus  ani  only. 
Occasionally  there  is  pain  on  defaecation,  and  rarely  a  little  blood-stained  discharge. 
Eczema  and  Pruritus  ani  in  a  woman  should  always  make  the  observer  at  least 
think  of  a  rectal  gonococcal  infection.  A  naked  eye  examination  of  the  rectum 
usually  suffices  one  in  making  a  diagnoisis,  as  a  microscopic  examination  of  the 
secretion  can  so  easily  fail  to  reveal  the  gonococcus.  The  mucous  membrane  is 
red  and  swollen ;  it  bleeds  easily  if  injured,  and  there  are  usually  several  erosions, 
some  of  which  maj^  be  covered  with  a  sort  of  membrane.  It  is  doubtful  whether 
true  ulceration  ever  occurs,  and  it  is  still  more  doubtful  whether  a  rectal  stricture 
can  follow  a  gonococcal  infection.  Only  the  lower  part  of  the  rectum  is  affected. 
The  process  is  slow  in  disappearing,  and  is  not  very  easy  to  cure.  The  rectum 
should  be  treated  in  exactly  the  same  way  as  the  male  urethra  is,  and  no  instru- 
ment passed  until  the  acute  and  subacute  stages  have  ended.  Then  a  proctoscope 
can  be  inserted,  and  the  erosions  cauterised  with  a  3  per  cent,  solution  of  silver 
nitrate. 

'  Finger  (1908),    "  Die  Geschlechtskrankheitcn."     II  Tfil.     Verlag  von  F.  Deuliclic. 

-  Sellei  (1907),  "  Orvosi  Hetilap,"  43. 

'  Oppenheim  u.  Low  (1905),  "  Virchows  Arcliiv.,"  clxxxii,  39. 

*  Bosenfeld  (1898),  '■  Bed.  klin.  Woch.,"  xxxv,  661. 


CHAPTER   XXXIV. 

COMPLICATIONS   OF  GONORRHOEA  DUE  TO  A  SPREAD 
BY  METASTASIS  OF  THE   ORGANISM. 

Tenosynovitis  and  Bursitis. 

A  tenosynovitis  may  occur  alone,  or  in  company  with  an  arthritis,  in 
which  case  the  tendon  sheaths  around  the  affected  joint  are  those  most 
frequently  affected.  Extensor  tendon  sheaths  are  more  often  affected  than 
flexor  ones,  and,  of  the  former,  the  extensor  tendons  of  the  hands  and  feet 
are  most  often  involved.  The  secreted  fluid  is  usually  serous,  rarely  purulent,  and, 
as  is  the  rule  in  all  gonococcal  lesions,  fibrous  tissue  formation  is  pronounced,  and 
unless  this  fact  be  borne  in  mind  in  all  cases  of  tenosynovitis,  most  troublesome 
adhesions  may  form.  A  tenosynovitis  may  set  in  very  quickly  after  the  onset  of 
the  urethritis.  I  once  had  a  case,  with  bilateral  tenosynovitis  of  the  extensor 
communis  digitorum,  which  was  well  marked  on  the  fifth  day  after  infection. 

Tenosynovitis  may  complicate  gonococcal  conjunctivitis  of  infants,  and  it  is 
not  at  all  uncommon  in  cases  of  vulvo-vaginitis  of  young  girls. 

In  the  treatment  of  all  metastatic  complications,  attention  should  first  be  paid 
to  the  site  of  inoculation,  which  is  usually  the  urethra.  Vaccines  are  especially 
useful,  and  should  be  administered  as  described  in  Chapter  XXXIX.  Operative  pro- 
cedure should  always  be  the  last  consideration,  and,  in  the  case  of  tenosynovitis, 
should  only  be  employed  when  there  is  suppuration.  In  all  ordinary  cases,  firm 
pressure  should  be  apphed  to  the  affected  part,  when  the  acute  inflammatory  stage 
has  vanished  under  cold  applications  or  ichthyol ;  but  exercises  should  be  com- 
menced as  soon  as  possible,  so  as  to  prevent  any  contraction  from  adhesions. 

Gonococcal  bursitis  is  rare,  except  in  those  cases  in  which  neighbouring  bursae 
of  a  joint  become  infected  by  direct  extension.  The  patellar  and  subcrural  bursae 
may  be  affected  alone,  and  I  have  also  seen  cases  of  trochanteric  and  ischial  bursitis. 
In  one  case  of  ischial  bursitis  under  my  care,  suppuration  set  in,  and  left  a  sinus 
from  the  skin  of  the  buttock,  which  took  a  long  time  to  heal. 

The  pain  in  the  Achilles  tendon,  of  which  complaint  is  so  frequently  made  in 


METASTATIC    COMPLICATIONS    OF   GONORRHOEA.  407 

gonorrhoea,  may  be  due  to  an  inflammation  of  the  bursae  in  this  region,  but  it  is 
more  often  due  to  inflammation  of  the  tendon  itself.  The  pain  complained  of  in  the 
heel  and  foot  is  usually  due  to  inflammation  of  the  os  calcis,  of  the  bursa  under- 
neath this  bone,  and  of  the  plantar  fascia. 

Inflammation  of  the  plantar  fascia  is  the  cause  of  flat  foot,  which  is  so  commonly 
met  with  in  patients  suffering  from  gonorrhoea.  It  has  been  especially  noticeable 
in  the  present  war,  owing  to  the  marching  which  has  had  to  be  done. 


Gonococcal  Arthritis. 

For  years  past,  there  has  been  continued  and  acute  discussion  as 
to  whether  gonococcal  arthritis  was  a  metastatic  lesion,  or  a  lesion  due 
to  the  gonotoxine.  The  reason  why  several  observers  held  the  latter  view,  was 
because  they  failed  to  find  the  gonococcus  in  the  fluid  which  they  drew  off.  I  have 
examined  the  fluid  from  nine  cases  of  gonococcal  arthritis,  in  every  one  it  was 
sterile.  In  those  cases  tested  for  the  presence  of  antibody  and  antigen,  the  former 
was  found,  but  not  the  latter.  The  reason  why  the  gonococcus  is  not  generally 
found  in  the  fluid,  is  that  it  remains  limited  to  the  synovial  membrane.  It  is  just 
the  same  with  the  tubercle  bacillus  in  a  cold  abscess.  The  organism  is  not  found 
in  the  pus,  but  in  the  wall  of  the  abscess.  It  is  now  almost  universally  agreed  that 
a  gonococcal  arthritis  is  a  metastatic  lesion. 

No  case  of  gonococcal  arthritis  should  be  treated  lightly,  because  a  joint 
affected  from  any  specific  cause  is  always  liable  to  become  secondarily  infected. 
If  anyone  has  seen  a  pyogenic  infection  of  a  gonococcal  joint,  the  picture  is  not 
likely  to  be  forgotten.  Within  a  few  days  of  the  joint's  becoming  purulent,  the 
patient  may  die,  and  should  the  case  not  terminate  fatally,  bony  ankylosis  is  all 
that  can  be  hoped  for. 

Gonococcal  arthritis  can  generally  be  prevented,  if  all  gonorrhoeal  patients 
are  strictly  forbidden  taking  any  exercise,  a  point  which  is  proved  by  the  enormous 
numbers  of  soldiers  who  have  been  invalided  home  during  this  present  war  with 
joint  trouble. 

Before  a  true  arthritis  becomes  manifest,  the  patient  usually  experiences 
fleeting  sharp  pains  in  the  joint  which  is  to  become  affected.  If  rest  is  ordered,  and 
if  vaccines  are  injected  without  delay,  the  progress  of  the  inflammation  may  be 
checked. 

The  statement  has  frequently  crept  into  writings  that  women  are  immune  from 
gonococcal  arthritis.  Such  is  far  from  being  the  case,  as  both  men  and  women  are 
equally  affected. 


408  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   GONORRHOEA. 

A  man  who  contracts  gonococcal  arthritis  is  practically  certain  to  have  a 
prostato-urethritis,  and  a  woman  is  certain,  at  least,  to  have  a  cervicitis.  More 
often  she  has  an  endometritis,  and  in  many  cases  she  has  a  salpingitis.  Therefore 
no  case  of  arthritis  should  be  treated,  without  the  main  attention  being  paid  to  the 
site  from  which  the  organisms  entered  the  blood  stream. 

It  must  not  be  forgotten  that,  although  we  generally  refer  to  adults  when 
speaking  of  gonococcal  arthritis,  the  complication  may  also  occur  in  cases  of  infantile 
gonococcal  conjunctivitis,  and  it  is  not  at  all  uncommon  in  cases  of  vulvo-vaginitis 
affecting  young  girls. 

An  arthritis  may  complicate  the  first  attack  of  gonorrhoea,  but  it  more  often 
starts  during  the  fiist  or  second  recurrence  of  the  uncured  original  attack.  Should 
the  patient  have  repeated  recurrences  of  his  urethritis,  and  an  arthritis  of  one  knee 
joint,  which  complicated  his  first  recurrence,  this  same  knee  joint  is  apt  to  light 
up  again  in  each  future  recurrence.  This  condition  of  aft'airs  is  quite  pathognomonic 
of  gonococcal  arthritis.  The  types  of  gonococcal  arthritis  allow  themselves  to  be 
conveniently  divided  into  four  classes  :  (1)  Hydrops  articuli ;  (2)  sero-fibrinous 
arthritis  ;    (3)  purulent  arthritis  ;    (-4)  phlegmonous  arthritis. 

Hydrops  articuli. — Usually  without  any  warning,  a  joint,  which  is  most 
commonly  the  knee,  becomes  suddenly  distended  with  fluid.  The  joint  is  not  even 
painful.  The  fluid  may  disappear  as  quickly  as  it  came,  recurrence  is  common, 
and,  as  the  amount  of  fluid  may  be  considerable,  repeated  sudden  distension  of  a 
joint  is  liable  to  lead  to  a  destruction  of  its  ligaments.  More  rarely  the  fluid  takes 
a  long  time  to  disappear.  In  these  cases,  if  the  distension  is  very  marked,  it  is 
imperative  to  tap  the  joint. 

A  joint  should  never  be  tapped  except  under  the  strictest  aseptic  precau- 
tions. The  knee  is  practically  the  only  joint  for  which  the  operation  has  to  be 
undertaken.  The  limb  is  extended,  and  a  Barker's  lumbar  puncture  needle  is 
inserted  between  the  external  condyle  of  the  femur  and  the  external  tuberosity 
of  the  tibia.  The  fluid  should  be  allowed  to  escape  only  slowly,  and,  after  it  has 
been  removed,  a  Martin's  rubber  bandage  should  be  applied  from  below  upwards, 
and  the  patient  should  be  kept  at  rest.  If  the  knee  is  not  bandaged  at  once,  it  may 
fill  up  again  with  fluid  in  an  hour  or  two.  Subcutaneous  injections  of  the  withdrawn 
fluid  in  the  region  of  the  affected  joint  has  never,  in  my  experience,  been  of  any 
benefit. 

The  synovial  membrane  and  capsule  remain  thin,  in  cases  of  Hydrops 
articuli. 

Arthritis  sero-fibrinosa. — This  is  by  far  the  most  common  form  of  gonococcal 
arthritis.     Both  the  synovial  membrane  and  capsule  are  usually  thickened.     The 


METASTATIC    COMPLICATIONS    OF   GONORRHOEA.     '  409 

withdrawn  fluid  loolcs  not.  unlike  serum,  and  it  is  called  fibrinous,  owing  to  the 
amount  of  contained  fibrin,  which  frequently  causes  the  fluid  to  clot. 

With  this  form  of  arthritis,  the  patient  usually  looks  very  pale  and  ill.  The 
muscles  around  the  joint  soon  become  atrophied,  and  any  of  the  focal  complications 
which  have  been  described  may  accompany  this  form. 

This  form  of  arthritis  is  very  liable  to  recur,  and  at  each  recurrence  the  capsule 
becomes  still  more  thickened.  Owing  to  the  amount  of  fibrin  which  is  formed, 
adhesions  are  liable  to  follow  the  subsidence  of  the  inflammation. 

The  purulent  arthritis  usually  arises  from  the  sero-fibrinous  form  becoming 
infected  with  pyogenic  cocci. 

Phlegmonous  arthritis,  which  was  so  christened  by  Konig,  is  an  arthritis  in 
which  the  capsule  and  the  periarticular  tissues  are  the  structures  most  aiYected. 
The  joint  is  often  markedly  swollen,  but  the  amount  of  fluid  in  it  is  very  small. 
This  form  of  arthritis  has  frequently  received  the  name  of  pseudo-membranous. 
As  the  inflammation  is  most  acute  in  the  periarticular  tissue,  the  subcutaneous 
tissue  is  oedematous,  and  the  skin  over  it  is  very  red  and  painful.  The  inflammation 
quickly  spreads  to  the  interior  of  the  joint,  and  destroys  all  the  Ugaments,  hence 
it  is  in  the  phlegmonous  arthritis  that  subluxation  of  the  tibia,  and  other  orthopaedic 
deformities  of  joints  are  most  likely  to  occur. 

In  phlegmonous  arthritis,  absolute  rest  should  be  enforced,  since,  owing  to  the 
acuteness  of  the  inflammation,  a  pyogenic  infection  is  apt  to  find  its  way  into  the 
joint.  Vaccines  should  be  injected  as  quickly  as  possible.  All  antiphlogistic 
measures  should  be  employed,  and  the  limb  fixed  in  that  position  in  which  bony 
ankylosis  would  least  impair  its  usefulness,  since  bony  ankylosis  is  the  result  to  be 
hoped  for. 

In  the  mild  cases  of  phlegmonous  arthritis,  and  in  the  chronic  cases  of  Arthritis 
sero-fihrinosa,  changes  in  the  joint  may  be  produced  which  become  absolutely 
indistinguishable  from  the  condition  that  is  called  osteoarthritis.  The  cartilage 
is  worn  away,  the  bony  surfaces  become  eburnated,  and  the  edges  develop  osteo- 
phytic  growths.  I  have  notes  of  three  cases  of  gonococcal  osteoarthritis  of  the  hip 
joint,  in  one  of  which  the  head  of  the  femur  has  already  been  dislodged  from  the 
acetabulum ;  and  of  two  cases  of  a  similar  condition,  affecting  the  knee  joint. 
Naturally,  treatment  in  such  cases  is  unavailing. 

Although  polyarticular  arthritis  is  not  uncommon  in  gonorrhoea,  the  mono- 
articular form  is  certainly  the  more  frequent.  As  a  rule,  not  more  than  two  or  three 
joints  are  affected  at  a  time,  although  several  may  be  affected  at  different  intervals. 

Owing  to  the  small  size  of  the  finger  and  toe  joints,  periarticular  changes  are 
practically  constant ;    and  as  these  almost  invariably  lead  to  a  chronic  thickening 


410  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   GONORRHOEA. 

of  these  tissues,  the  patients  usually  have  a  permanent  broadening  of  their  fingers 
and  toes,  at  the  metatarso  and  metacarpo-phalangeal  joints. 

Any  patient  who  has  had  a  gonococcal  arthritis  is  very  liable  to  suffer  for  years 
afterwards  with  wliat  may  be  called  arthralgia.  Such  patients  are  apt  to  notice 
changes  in  the  weather  and  changes  in  temperature.  It  is  well  to  bear  this  arthralgia 
in  mind,  as  it  is  often  mistaken  for  a  recurrence  of  the  arthritis. 

The  local  application  of  unguentum  iodex,  or  unguentum  guaiacol  (10  to  40  per 
cent.),  quickly  disperses  the  arthralgic  pains. 

The  knee  is  far  and  away  the  most  frequent  joint  to  be  afiected — indeed,  Hydrops 
articuli  is  unknown  in  any  other.  After  the  knee,  come  the  ankle  and  wrist  joints. 
The  metacarpo-  and  metatarsophalangeal  joints  are  frequently  affected,  also  the 
other  small  joints  of  the  foot. 

Arthritis  of  the  joints  of  the  upper  extremities,  other  than  those  already 
mentioned,  is  not  very  common.  The  elbow  is  affected  more  often  than  the 
shoulder  ;  in  many  cases  it  is  the  only  joint  affected,  and  there  is  usually  a  marked 
wasting  of  the  muscles  around  the  joint. 

When  the  hip  joint  is  affected,  it  is  usually  the  only  joint  that  is  involved.  Any 
joint  may  be  affected,  but  arthritis  in  other  than  those  already  mentioned  is  rare  ; 
but  there  is  one  which  requires  special  mention,  i.e.,  Spondylitis  deformans. 

1  have  had  altogether  five  cases  of  Spoiulylitis  deformans  under  my  care. 
Spondylitis  deformans  is  an  uncommon  condition,  and  is  said  to  be  of  varied 
aetiology.  It  starts  as  an  inflammation  of  the  ligaments  of  the  vertebrae,  which 
leads  to  contraction  of  the  former,  and,  finally,  to  ankylosis  of  the  latter.  A 
section  or  sections  of  the  spine,  or  even  the  whole  vertebral  column,  may  be 
affected,  in  which  case  the  movements  of  the  ribs  may  be  stopped  entirely,  with 
the  risk  of  subsequent  lung  trouble. 

Unfortunately  nothing  is  certain  in  medicine,  and  if  a  statement  is  made, 
something  will  be  bound  to  crop  up  the  next  moment  to  contradict  it ;  but  1  cannot 
help  feeling  that  gonorrhoea  is  the  one  and  only  cause  of  Spondylitis  deformans. 
In  all  my  cases, the  trouble  started  during  a  recurrent  attack  of  a  b5'gone  gonorrhoea; 
in  every  case,  one  or  more  of  the  joints  in  the  body  were,  or  had  been  affected,  and 
all  five  were  men.  Unless  the  case  is  obtained  early,  treatment  is  unavailing,  and 
only  one  of  my  cases  was  I  able  to  cure. 

Case  57. — Patient,  a  man  aged  27,  contracted  gonorrhoea  seven  years  ago,  which 
disappeared  without  complications.  First  recurrence  four  years  later,  which  likewise 
vanished  without  trouble.  The  second  recurrence  began  in  Januar}^  1913,  and 
fourteen  days  after  the  onset  of  the  discharge,  the  patient  developed  an  arthritis 
of  the  left  tarso-metatarsal  joints,  which  spread  in  the  following  order  to  other 


METASTATIC    COMPLICATIONS   OF   GONORRHOEA.  411 

joints  :  right  l^nee,  left  knee,  left  temporo-maxillary,  both  shoulder  and  cervico- 
vertebral  joints. 

Under  local  treatment  and  injections  of  an  autogenous  vaccine,  the  patient 
improved,  except  that  pain  down  the  whole  spine  set  in  and  increased.  A  mixed 
vaccine  was  made  of  the  organisms  obtained  from  the  prostatic  secretion,  with  the 
result  that  a  severe  epididymitis  followed,  and  the  patient  became  worse  than  he 
had  ever  been  before. 

I  saw  the  patient  for  the  first  time  in  August,  1913,  by  which  time  he  had  lost  over 
three  stones  in  weight ;  he  walked  slowly  with  the  aid  of  a  stick,  had  a  pronounced 
stoop,  head  was  thrown  forwards,  and  shoulders  were  raised  to  avoid  moving  spine. 
On  examination,  he  was  found  to  have  a  chronic  prostato-urethritis  and  vesiculitis, 
an  acute  teno-vaginitis  of  the  extensor  sheath  of  the  left  wrist ;  the  spine  was 
tender  but  quite  movable.  Under  the  usual  local  treatment,  coupled  with  the 
internal  administration  of  potassium  iodide,  and  daily  injections  of  a  sensitised 
gonococcal  vaccine  up  to  1,000,000,000,  with  a  further  weekly  injection  of  the 
maximum  dose,  the  patient  completely  recovered,  and  within  a  few  weeks  the 
movements  of  the  spine  were  natural  and  elicited  no  pain. 

Treatment. — The  one  word  which  should  be  in  every  physician's  mind,  when 
he  is  called  upon  to  treat  a  case  of  gonococcal  arthritis,  is — adhesion.  The  thought 
of  adhesions  suggests  exercises,  and  as  to  when  exercises  should  be  commenced, 
hardly  any  two  observers  are  of  the  same  mind.  Too  early  movements  are  very 
apt  to  cause  a  recurrence,  and  the  formation  of  adhesions  is  always  more  marked  in 
the  recurrent  attacks  than  in  the  first  attack  of  arthritis.  I  think  it  wiser  myself  to 
keep  the  joint  at  rest,  until  all  the  gonococci  in  it  have  been  vanquished,  and  this 
can  usually  be  ascertained  by  the  absence  of  a  focal  reaction  after  the  last  injection 
of  vaccine.  Then  it  is  safe  to  commence  massage  and  exercises.  In  all  joint  cases, 
sodium  salicylate  and  potassium  iodide  should  be  given  internally. 

When  the  arthritis  is  acute,  cold  applications  should  be  used,  and,  when  the 
acute  stage  has  passed,  painting  on  tincture  of  iodine  or  oil  of  wintergreen  is  useful. 

Other  points  concerning  treatment  have  already  been  dealt  with,  but,  before 
closing  this  part  of  the  subject,  mention  must  be  made  of  Bier's  treatment.  Bier's 
treatment  may  be  adopted  in  any  stage,  and,  if  properly  used,  it  will  quickly  heal 
a  joint  in  the  acute  and  subacute  stages,  and  will  prevent  adhesions  from  forming 
in  the  chronic  stage. 

In  the  acute  stages,  the  bandage  must  remain  applied  for  every  twenty  hours 
out  of  the  twenty-four,  while  in  the  chronic  stage  it  should  not  remain  in  contact  for 
more  than  an  hour  at  a  time.  The  great  advantage  of  Bier's  treatment  is  that 
exercises  can  be  started  earlier. 


412  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   GONORRHOEA. 

The  best  bandage  to  use  is  an  elastic  one,  about  2^  inches  wide,  and  it  should 
be  commenced  with  two  or  three  turns  well  to  the  proximal  side  of  the  affected 
joint,  and  then  carried  right  down  the  limb.  When  the  bandage  is  applied  for  as 
long  as  twenty  hours,  oedema  may  result.  That  does  not  matter,  but  it  is  essential 
to  avoid  pain,  and  to  prevent  the  limb  from  becoming  blue.  The  pain  which  is 
experienced  when  the  bandage  is  fii'st  put  on  soon  dies  down,  if  the  bandage  has 
been  applied  properly.  The  greatest  advantage  of  Bier's  treatment  rests  in  the  fact 
that  it  is  not  necessary  to  keep  the  joint  absolutely  at  rest  and  stiff.  The  joint 
may  also  be  moved  when  the  bandage  is  changed,  hence  the  risk  of  formation  of 
adhesions  becomes  practically  nil,  and  the  muscles  around  the  joint  do  not  atrophy. 
Bier's  treatment  in  gonococcal  arthritis  cannot  be  too  warmly  recommended. 
Atophan  (phenyl-quinohn-carboxyhc  acid)  given  internally,  is  sometimes  beneficial 
in  cases  of  gonococcal  arthritis  : — 

R    Atophan         . .         .  .         . .         . .         . .     gr.  vij 

Sod.  bicarbon.  . .  . .  . .  . .     gr.  vij 

M.  f.  pulv.  m  cachet. 

One  cachet  to  bo  taken  before  every  meal. 

Guaiacol  carbonate  is  also  a  useful  drug,  and,  in  all  subacute  and  chronic 
cases,  increasing  doses  of  potassium  iodide  shoukl  be  prescribed. 

Gonorrhoea  of  the  Muscles. 

There  is  no  doubt  that  a  true  gonococcal  myositis  may  arise  by  a  direct 
extension  of  the  mischief  from  a  joint.  But  the  muscular  wasting  which  so 
rapidly  occurs  around  an  affected  joint  is  more  often  due  to  the  gonotoxine,  which 
causes  a  trophoneuritis. 

The  so-called  muscidar  rheumatism  or  gonococcal  myalgia  may  be  diffuse, 
or  limited  to  one  group  of  muscles,  or  even  to  one  muscle.  It  is  not  a  true  gono- 
coccal myositis,  but  a  gonotoxic  lesion,  which,  as  a  rule,  produces  no  changes  in  the 
muscle  or  muscles  involved. 

A  true  gonococcal  myositis  may  pick  out  any  muscle.  It  gives  rise  to  a  localised 
inflammatory  swelling,  which  is  acutely  painful.  After  the  inflammation  has 
vanished,  atrophy  may  result. 

Gonorrhoea  of  the  Bones. 

The  periosteum  is  the  part  most  frequently  affected,  and  a  secondary  involve- 
ment is  far  more  common  than  a  primary  one.  A  tenosynovitis  of  the  tibialis 
posticus  is   almost   certain   to  lead  to  a  periostitis.     A  periostitis  usually  results 


METASTATIC    COMPLICATIONS   OF   GONORRHOEA.  413 

from   a   trochanteric   bursitis,    and   the   periosteum   is   always   liable  to   become 
affected  in  severe  cases  of  arthritis. 

A  primary  periostitis  may  occur  anjrwhere. 

GONORRHOEAL   DISEASES    OF   THE   NeRVOUS    SySTEM. 

Peripheral  neuritis  is  not  at  all  an  uncommon  complication,  but  a  gonococcal 
infection  of  the  central  nervous  system  is  very  rare.  A  peripheral  neuritis  may 
be  the  only  symptom  of  a  metastatic  infection,  but,  as  is  the  case  in  the  majority 
of  the  metastatic  lesions,  the  lesions  usually  accompany  an  arthritis,  succeeding 
more  often  than  preceding  the  joint  trouble. 

Although  peripheral  neuritis  is  here  being  described  as  a  metastatic  lesion,  no 
actual  proof  has  yet  been  brought  forward  that  it  is  due  to  the  direct  presence  of 
the  gonococcus.  It  may  be  due  to  the  gonotoxine,  but,  as  it  behaves  clinically  like 
all  other  metastatic  lesions,  I  am  most  inclined  myself  to  ascribe  its  origin  to  the 
organism  itself.  The  neuritis  may  affect  a  single  nerve  or  many  nerves,  and,  in 
nearly  every  case,  it  is  one  or  more  of  the  nerves  of  the  lower  extremity  that  are 
affected.  In  my  experience,  the  most  common  gonococcal  neuritis  is  a  neuritis  of 
the  trunk  of  the  sciatic  nerve,  and  I  have  never  yet  seen  a  case  in  which  the  sciatica 
was  not  accompanied  by  an  arthritis  of  the  knee  or  ankle,  on  the  same  or  on  both 
sides.  Sciatica  accompanying  an  arthritis  of  the  hip  is  generally  secondary  in 
nature,  and,  as  a  rule,  becomes  marked  only  when  osteo-arthritic  changes 
have  set  in.  A  very  troublesome  form  of  neuritis  is  that  which  affects  the 
genito-crural  nerve.  It  appears  to  me  to  be  more  persistent  and  less  influenced 
by  treatment  than  neuritis  of  the  sciatic  nerve,  and,  owing  to  the  course  run  by  the 
nerve,  an  inflammation  of  it  may  be  the  start  of  a  sexual  neurasthenia.  Only  once 
have  I  seen  a  case  of  gonococcal  polyneuritis.  The  upper  extremities  were  more 
affected  than  the  lower  ;  there  was  marked  muscular  wasting  of  the  arms.  The 
patient  was  also  suffering  from  a  pyelonephritis. 

So  far  as  the  central  nervous  system  is  concerned,  a  few  cases  of  transverse 
myelitis  have  been  described.  Gonococcal  meningitis  appears  to  be  very  rare,  but 
cases  of  hemiplegia  have  from  time  to  time  been  reported. 

Gonorrhoea  of  the  Heart  and  Blood-Vessels. 

The  name  of  Ricord  should  stand  pre-eminent  in  the  roll  of  honour  of  those 
who  have  added  to  our  knowledge  of  venereal  disease.  He  lived  at  a  time  when 
pathology  and  bacteriology  had  not  opened  for  research  the  paths  which  exist  to- 
day.    He  tore  aside  the  veil  of  fallacies  with  which  Hunter's  work  had  dinmied  the 


414  THE    BIOLOGY,    CLINICAL    ASPECT   AND   TREATMENT   OF   GONORRHOEA. 

true  view  of  this  branch  of  medical  science.     Ricord  was  the  first  to  recognise 
that  gonorrhoea  could  cause  an  endocarditis  and  pericarditis. 

Endocarditis  is  a  rare  complication  of  gonorrhoea,  and  one  of  the  reasons  for 
this  is  that,  in  many  cases,  the  gonococcus  has  failed  to  be  found.  The  gonococcus 
has,  no  doubt,  been  the  predisposing  cause,  but  the  destruction  of  the  cardiac 
valves  has  been  produced  by  a  secondary  infection.  These  cases  come  under  the 
care  of  the  general  physician  rather  than  under  that  of  the  venereal  specialist.  I 
have  seen  three  cases  of  gonococcal  endocarditis.  In  two,  a  pure  culture  of  gono- 
cocci  was  obtained  during  life  from  the  peripheral  blood  stream,  and,  post-mortem, 
from  the  heart's  blood.     In  the  third  case  the  cultures  grew  streptococci  as  well. 

I  was  able  to  make  a  microscopic  examination  of  the  cardiac  valves  in  one  of 
the  two  former  cases,  and  the  vegetations  contained  practically  nothing  else  but 
gonococci. 

In  many  of  the  reported  cases  of  gonococcal  endocarditis,  especially  in  the 
earlier  ones,  the  cultiu-es  remained  sterile.  This  is  undoubtedly  due  to  the  fact 
that  an  appropriate  medium  was  not  employed,  therefore  it  must  not  be  assumed 
that  they  were  not  true  cases  of  gonococcal  endocarditis. 

I  have  mentioned  these  various  points  in  order  to  draw  more  attention  to  this 
complication,  which  I  am  certain  is  more  common  than  is  thought  to  be  the  case. 
Cases  do  not  run  an  invariably  fatal  course,  and,  if  caught  early,  a  great  deal  can 
be  done  by  treatment,  especially  with  sensitised  vaccines.  Many  patients  suffering 
from  gonorrhoea  have  a  transient  cardiac  lesion — stabbing  pain  in  the  chest, 
increased  cardiac  action,  and  perhaps  a  faint  pericardial  rub. 

If  every  observer  carefully  examined  the  heaits  of  all  his  patients  suffering 
from  gonococcal  arthritis,  he  would  be  surprised  at  the  comparatively  large  per- 
centage which  showed  a  disturbance  of  some  kind  or  other. 

Benign  gonococcal  endocarditis  is  nnich  more  common  than  malignant 
gonococcal  endocarditis.  The  former  is  almost  invariably  associated  with  either 
rheumatism  or  arthritis  of  gonococcal  origin,  and  it  is  very  difficult,  unless  the 
urethra  is  examined,  to  distinguish  this  form  of  endocarditis  from  the  common 
so-called  rheumatic  endocarditis. 

The  malignant  gonococcal  endocarditis  usually  causes  death,  before  even  the 
diagnosis  of  gonorrhoea  has  been  made.  Whether  it  is  the  rule  or  not  I  cannot 
sa}',  but  anyhow,  in  the  three  cases  which  I  saw,  the  patients  had  no  other  com- 
plication, and,  in  the  case  in  which  I  was  able  to  examine  the  cardiac  valves,  I  made 
microscopic  sections  of  the  prostate  and  seminal  vesicles,  but  both  were  normal. 

According  to  Schlagenhaufer,  the  valves  most  frequently  involved  are,  first, 
the  aortic,  then  the  mitral,  and  only  very  occasionally  the  tricuspid  and  pulmonary. 


METASTATIC    COMPLICATIONS   OF   GONORRHOEA.  415 

The  spleen  is  always  swollen,  and  there  may  be  an  acute  toxic  nephritis  or  renal 
infraction. 

In  any  case  of  endocarditis,  it  has  frequently  been  recommended  to  inject 
intravenously  0'02  to  0'04  c.c.  of  collargol,  but  of  its  use  in  gonococcal  endocarditis 
I  have  had  no  practical  experience. 

What  has  already  been  said  about  endocarditis,  applies  equally  well  to  peri- 
carditis, but  it  should  be  remembered  that,  although  a  patient  who  has  a  gonococcal 
pericarditis  is  almost  certain  to  have  an  endocarditis,  the  pericardial  lesion  may 
be  the  only  one  that  can  be  diagnosed  cHnically. 

A  gonococcal  phlebitis  is  very  rare  ;  the  vein  which  is  most  commonly  affected 
is  the  internal  saphenous  vein.  The  dorsal  veins  of  the  penis  may  be  affected  in 
severe  cases  of  gonorrhoea,  and,  in  most  cases  of  gonorrhoea,  a  lymphangitis  of  the 
penis  occurs,  and  in  almost  every  case  the  inguinal  lymphatic  glands  are  enlarged 
and  painful. 

A  microscopic  section  of  lymphatic  glands  removed  from  the  inguinal  region, 
during  an  acute  attack  of  urethritis,  always  reveals  a  typical  inflammatory  adenitis. 
Rarely  any  mention  is  made  of  the  fact  that  inguinal  adenitis  accompanies 
practically  every  case  of  acute  gonorrhoea,  with  the  result  that  the  diagnosis  of 
syphihs  is  made  almost  every  day,  from  not  reahsing  this  fact. 


2d 


CHAPTER  XXXV. 
NON-GONOCOCCAL  URETHRITIS. 

This  is  one  of  the  most  interesting,  most  difficult,  and  least  understood 
subjects  with  which  one  has  to  deal.  Several  conditions  may  cause  a  urethritis, 
but  a  non-gonococcal  urethritis  is  always  rare.  The  discharge  from  a  balanitis, 
from  a  soft  sore  infection,  and  from  a  syphilitic  sore,  especially  if  the  patient  has 
a  tight  foreskin,  may  cause  a  urethritis.  In  these  cases,  the  aetiology  is  obvious,  but 
it  is  not  so  in  the  majority  of  cases. 

Phosphaturia  and  oxaluria  may  give  rise  to  a  urethritis,  but,  if  the  crystals  irritate 
the  mucous  membrane  of  the  urethra,  they  are  certain  to  have  irritated  the 
epithelium  of  the  bladder,  hence  these  cases  always  complain  of  frequency  of 
mictiu'ition.  The  urine  in  both  glasses  is  always  thick,  so  that  an  unwary  observer 
may  diagnose  an  acute  posterior  gonococcal  urethritis.  Frequently  the  urine  does 
not  become  clear  on  adding  acetic  acid,  a  point  which  may  further  add  to  his 
difficulty. 

Phosphaturia  is  a  very  important  condition,  as  it  not  infrequently  complicates 
an  old  standing  gonococcal  infection  which  is  most  rebellious  to  treatment.  Such 
a  state  of  affairs  is  always  met  with  in  a  certain  type  of  individual.  The  patient 
is  very  neurotic  ;  he  takes  his  gonococcal  infection  very  much  to  heart,  and  severe 
cases  may  even  have  suicidal  notions.  Whether  the  phosphatmia  is  post  hoc  or 
propter  hoc  I  cannot  tell,  all  I  know  is  that  the  phosphaturia  and  the  psj'chic 
condition  are  associated. 

The  thickness  of  the  urine  in  phosphaturia  is  due  to  the  precipitation  of 
insoluble  phosphates,  which  is  dependent  upon  an  increase  of  the  alkalinity,  or  a 
decrease  of  the  acidity  of  the  urine.  The  insoluble  phosphates  are  mainly  the 
calcium  salts  Ca..  (PO^.),,  and  these  are  mixed  with  magnesium  salts.  The 
carbonates  are  especially  abundant  after  a  fruit  meal,  or  after  drinking  large 
quantities  of  lemonade. 

Since  motor  cycling  has  become  so  popular,  one  occasionally  sees  cases  of 
urethritis  caused  by  it.  Ordinary  cycling,  and  even  horse  riding  may  very  rarely 
produce  an  attack.     Strong  antiseptics  are  a   more  common  cause  of  urethritis 


NON-GONOCOCCAL    URETHRITIS.  417 

than  is  generally  supposed.  The  urethritis  of  gonococcal  origin  is  often  kept  going 
by  using  too  strong  solutions.  A  test  which  is  often  practised,  to  see  whether  a 
gonococcal  attack  is  cured  or  not,  is  to  inject  a  strong  solution  of  an  antiseptic. 
If  a  discharge  is  produced  or  increased,  the  patient  still  has  gonorrhoea,  if  not,  he 
is  cured. 

There  are  many  men  who  have  never  had  a  urethritis  who  would  speedily 
develop  one  after  such  a  test ;  therefore,  how  much  more  likely  must  this  be  the 
case  in  a  patient  who  has  been  already  over-treated.  Many  men  make  a  rule  of 
injecting  themselves  with  Condy's  fluid  directly  after  having  had  connection,  and 
I  have  seen  several  cases  in  which  an  acute  discharge  has  been  produced  by  such  a 
measure.  Either  the  solution  was  undiluted,  or  the  erection  persisted  while  the 
injection  was  being  carried  out.  Metschnikoff's  33  per  cent,  calomel  ointment, 
which  is  commonly  used  as  a  protection  against  syphiUs,  may  likewise  set  up  a 
transient  urethritis,  and,  in  passing,  I  may  state,  that  it  is  not  so  good  a  protection 
as  it  is  thought  to  be. 

Coitus  interruptus  and  chronic  constipation  may  be  the  cause  of  a  non- 
gonococcal urethritis,  especially  if  the  patient  has  had  a  previous  urethritis. 

These  cases  of  what  may  be  called  traumatic  urethritis  can  usually  be  diagnosed 
by  the  facts  that  there  is  no  incubation  period,  that  the  acme  is  reached  between 
the  second  and  the  third  day,  and  that  it  then  begins  to  abate  without 
treatment. 

The  increased  secretion  of  mucin  which  is  so  common  after  a  gonococcal 
infection,  and  about  which  most  patients  are  alarmed,  is  an  occurrence  which 
requires  very  special  mention. 

If  a  patient  has  been  cured  of  his  gonorrhoea  by  frequent  douchings  with 
strong  antiseptics,  by  the  passage  of  medicated  bougies,  and  by  somewhat  severe 
instrumentation,  he  is  very  liable  to  have  a  discharge  of  mucin  which  may  persist 
for  months,  and  even  years. 

The  mucin  discharge  is  clear  and  sticky.  It  quickly  forms  clouds  in  the  urine, 
which  are  increased  by  the  addition  of  acetic  acid.  Sometimes  the  secretion 
contains  a  mucinoid  substance  which  is  soluble  in  acetic  acid.  This  mucinoid 
substance  has  strong  reducing  properties,  and  is  more  commonly  met  with  in 
cystitis  than  in  urethritis.  The  clear  discharge  is  most  marked  in  the  morning  on 
rising,  but  I  have  seen  cases  in  which  it  has  persisted  throughout  the  day.  The 
mucin  comes  partly  from  the  prostate  and  partly  from  the  lu'ethra.  Frequent 
erections,  onanism,  active  exercise,  and  alcohol  are  very  apt  to  increase  it.  The 
importance  of  this  mucinous  urethritis  lies  in  the  fact  that  the  suflterer  still  thinks 
Ms  gonorrhoea  is  not  cured,  consequently  he  consults  one  doctor  after  another, 

'  2d2 


418  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   GONOREHOEA. 

probably  receiving  treatment  from  each.  The  result  is,  that  as  the  jirime  cause  is 
irritation,  further  treatment  only  tends  to  aggravate  the  condition. 

Urethral  injections  of  bismuth  sometimes  allay  the  irritation,  but  they  should 
not  be  persisted  in  for  long.  Keeping  the  bowels  well  open  checks  the  secretion, 
and  this  can  be  still  further  aided  by  giving  the  potassium  citrate  and  hyoscyamus 
mixture  internally.  A  ui'ethritis,  and  even  an  epididymitis,  may  occur  in  infectious 
fevers,  and  this  brings  me  on  to  describe  those  cases  produced  by  local  bacillary 
infections.  Almost  any  organism  may  produce  a  urethritis,  but,  in  my  experience, 
the  most  common  infections  are  those  produced  by  the  bacillus  coli,  by  a 
diphtheroid,  streptococcus,  and  staphjdococcus,  and  Micrococcus  catarrhalis.  Many 
of  these  infections  result  from  sexual  intercourse. 

It  must  be  remembered  that  the  bacillus  coli  is  not  at  all  an  uncommon  cause 
of  abscesses  in  Bartholin's  glands. 

Silver  salts,  in  my  experience,  are  apt  to  aggravate  these  non-gonococcal  cases 
of  bacillary  urethritis,  and  I  always  prefer  to  use  injections  of  boracic  acid,  quinine, 
or  very  dilute  solutions  of  the  perchloride  or  biuiodide  of  mercury. 

The  role  the  so-called  inclusion  bodies  play  in  causing  a  urethritis  has  not  yet 
been  settled. 

Halberstiidter  and  v.  Prowazek^  -  have  described  certain  inclusion  bodies  in  the 
epithelial  cells  from  cases  of  chronic  urethritis  which  they  consider  to  be  parasites. 
These  observers,  moreover,  state  that  the  bodies  seen  in  the  epithelial  cells  from  the 
urethra  are  the  same  as  those  seen  in  the  epithelial  cells  of  the  conjunctiva  from 
cases  of  trachoma.     These  parasites  are  thought  to  be  chlamydozoa. 

Several  observers  have  confirmed  Halberstadter  and  v.  Prowazek's  work, 
especially  so  far  as  trachoma  is  confirmed. 

These  inclusion  bodies  have  been  found  in  the  conjunctiva  of  newly-born 
infants,  and  the  infection  doubtless  was  conveyed  during  the  birth  of  the  child, 
in  the  same  manner  as  the  gonococcal  infection. 

Apes  have  been  infected  on  the  conjunctiva  with  material  obtained  from  a 
human  vagina.^  *  Therefore  it  is  highly  suggestive  that  these  inclusion 
bodies  are  parasites,  and  that  they  can  cause  a  urethritis  as  well  as  a  conjunctivitis. 
Fritsch^  has  succeeded  in  inoculating  a  monkey's  conjunctiva  wth  the  secretion 
from  a  urethra  which  was  infected  wth  these  inclusion  bodies;  and  Heymann^  has 
further  proved  that  the  genitals  of  apes  can  also  be  successfully  inoculated  from 
human  material. 

The  special  staining  properties  of  these  inclusion  bodies  have  yet  to  be  worked 
out,  as  up  to  the  present  only  Giemsa's  stain  has  been  used.  The  chemistry  of 
Giemsa's  stain  is  so  complicated  and  so  little  understood,  and  its  staining  action  is  so 


NON-GONOCOCCAL   URETHRITIS.  419 

uneven,  that  it  is  impossible  to  draw  any  conclusions  from  the  results  obtained. 
According  to  Halberstadter  and  v.  Prowazek,  the  inclusion  bodies  stain  red  with 
Giemsa ;  and  according  to  Lindner,  blue.  Micro-chemical  means  would  soon  settle 
the  point  as  to  whether  these  inclusion  bodies  are  parasitic  or  not. 

'  Halberstaedtcr  u.  v.  Prowazek  (1909),  "  Deutsche  med.  Woob.,"  x.xxv,  764. 

-  Ibid.  (1909),  "  Bcrl.  klin.  Woch.,"  xlvi,  1839. 

3  Lindner  (1910),  "  Wien.  klin.  Woch.,"  xxiii,  283. 

*  Ibid.  (1911),  "V.  Graefes  Arch.  f.  Ophthalm.,"  Ixxviii,  345. 

'  Fritsoh  (1910),  '•  v.  Graefes  Arch.  f.  Ophthahn.,"  Ixxvi,  547. 

«  HejTnann  (1910),  "  Bed.  klin.  Woch.,"  xlvii-  663. 


CHAPTER  XXXVI. 
GONORRHOEAL  DISEASES  OF  THE  EYES. 

Conjunctivitis. 

Gonococcal  conjunctivitis  should  be  divided  into  two  classes — (a)  adult ;  (6) 
infantile. 

Adtilt  Gonococcal  Conjunctivitis. 

Conjunctivitis,  in  the  adult,  may  be  due  either  to  the  gonotoxine,  or  to  the 
gonococcus  itself.  If  due  to  the  former,  the  condition  is  bilateral ;  and,  if  due  to 
the  latter,  the  condition  is  unilateral.  The  gonotoxic  conjunctivitis  gradually 
disappears  under  appropriate  treatment  of  the  urethra,  and  within  a  few  days  of 
the  administration  of  a  vaccine.  A  toxic  dose  of  a  vaccine  may,  on  the  other  hand, 
give  rise  to  the  condition.  Bathing  the  eyes  with  cold  water,  or  with  a  weak 
boracic  solution,  is  all  that  is  necessary.  The  conjunctivitis  due  to  the  gonococcus 
may  be  a  very  serious  affair,  therefore  it  should  be  diagnosed  and  treated  as  early 
as  possible.  At  first  the  symptoms  are  those  of  gonotoxic  conjunctivitis,  but  in 
a  few  hours  the  inflammation  becomes  much  more  acute,  and  the  photophobia 
becomes  intense.  About  twenty-four  hours  later,  the  conjunctiva  is  markedly 
swollen,  and  a  discharge  becomes  evident;  at  first  serous  in  nature,  and  then 
pundent.  Owing  to  the  swelling  of  the  conjunctiva,  the  lids  do  not  meet,  and  the 
patient  can  scarcely  open  them.  The  conjunctiva  of  the  lids  becomes  covered 
with  a  membrane,  and  bleeds  easily  when  the  latter  is  brashed  away.  By  this 
time,  the  skin  surrounding  the  eye  is  red  and  oedematous,  and  the  pre-auricular 
lymphatic  gland  is  swollen  and  painful.  If  allowed  to  continue,  the  purulent 
discharge  quickly  causes  a  destruction  of  the  conjunctiva,  the  cartilage  of  the  upper 
lid  becomes  soft,  there  is  a  marked  formation  of  new  blood  vessels,  and  the  cornea 
now  becomes  attacked.  If  the  cartilage  of  the  upper  lid  is  affected,  there  is  always 
the  danger,  when  the  fibrous  tissue  formation  begins,  after  resolution  sets  in,  that 
the  upper  lid  may  remain  permanently  thickened,  and  this  leads  to  a  condition  of 
what  is  usually  called  false  ptosis.     The  ptosis  is  probably  due  to  the  damage  and 


GONORRHOEAL   DISEASES    OF   THE    EYES.  4:21 

destruction  of  some  of  the  tendinous  fibres  of  the  levator  palpebrae  superioris.  The 
swelling  of  the  lower  lid  may  cause  an  ectropion,  but  it  is  very  seldom  that  it 
remains  permanent. 

One  of  the  most  remarkable  points  about  gonococcal  conjunctivitis  is,  that 
the  lachrymal  sac  never  becomes  affected.  There  must  be  some  peculiarity  in  the 
secretion  from  the  mucous  membrane  of  the  sac,  the  knowledge  of  which  might 
reveal  an  absolutely  complete  cure  for  gonorrhoea. 

The  danger  of  gonococcal  conjunctivitis  is  not  the  damage  done  to  the  con- 
junctiva, but  the  damage  which  is  certain  to  result  if  the  cornea  becomes  involved. 
Within  a  few  hours  of  the  commencement  of  a  keratitis,  the  cornea  may  be  ulcerated 
right  through,  and  the  iris  may  be  prolapsed. 

Even  in  mild  cases  of  keratitis,  a  leucoma  is  bound  to  residt,  and  this  often 
blocks  the  vision  of  that  eye. 

If  the  iris  prolapses,  and  a  staphyloma  forms,  there  is  always  the  danger  of  a 
supervention  of  a  secondary  glaucoma.  In  ver}^  bad  cases,  a  panophthalmitis  may 
occur. 

Gonococcal  conjunctivitis,  in  the  adult,  ought  always  to  be  prevented,  hence 
every  patient  who  contracts  gonorrhoea  ought  to  be  warned  against  touching  his 
eyes  with  his  fingers,  or  with  any  dirty  handkerchief,  piece  of  rag,  or  towel.  If 
conjunctivitis  has  begun,  the  first  consideration  should  be  given  to  the  unaffected 
eye,  and  the  healthy  eye  is  best  protected  by  what  is  called  a  BuUer's  shield,  which 
is  simply  a  watch  glass,  fixed  peripherally  with  strapping. 

In  the  affected  eye,  the  lids  shoidd  be  prevented  from  sticking  together  by 
applying  a  little  boric  ointment  to  them.  The  whole  of  the  conjunctiva  should 
be  washed  out  very  gently,  at  intervals  of  a  quarter  of  an  hour  to  an  hour,  night 
and  day,  with  a  weak  solution  of  potassium  permanganate.  The  colour  of  the 
solution  should  never  be  deeper  than  that  of  ordinary  red  blotting  paper.  The 
conjunctiva  should  never  be  touched  or  wiped  with  w^ool  or  any  other  absorbent — 
for  fear  of  breaking  its  surface,  and  thereby  causing  an  ulcer. 

As  the  continual  passage  of  antiseptics  over  the  inflamed  skin  may  readily  lead 
to  a  dermatitis,  from  which  a  secondary  infection  may  arise,  and  may  ultimately 
reach  the  eye,  the  inflamed  area  should  be  anointed  with  simple  boric  ointment. 

Although  patients  of  the  present  day  object  to  leeches,  there  is  no  other  means 
so  satisfactory  for  reducing  the  inflammation  as  the  application  of  one  or  two  to 
the  temple  on  the  affected  side.  Failing  leeches,  ice  must  be  used.  The  patient 
should  be  instructed  to  open  his  eye  as  widely  as  possible  and  to  move  his  lids 
occasionally,  so  as  to  prevent  the  constant  pressure  of  a  lid  at  one  point  breaking 
through  the  conjunctiva. 


422  THE   BIOLOGY,    CLINICAL    ASPECT   AND    TREATMENT   OF   GONORRHOEA. 

In  cases  which  are  complicated  by  keratitis,  the  treatment  will  depend  upon 
whether  there  is  a  simple  iritis,  or  upon  whether  there  is  a  likelihood  of  Descomet's 
membrane  giving  way.  In  the  former,  when  the  iris  is  practically  bound  to 
become  attached  to  the  cornea,  the  pupil  should  be  made  as  large  as  possible, 
therefore  atropine  should  be  used. 

In  the  latter,  where  there  is  the  danger  of  the  iris  prolapsing,  and  of  the  lens 
becoming  dislocated,  the  wider  the  pupil  is,  the  more  atropine  is  naturally  contra- 
indicated,  and  eserine  is  called  for.  Moreover,  on  the  eye  should  be  maintained 
a  gentle  pressure,  which  should  only  be  removed  when  the  eye  is  hourly  washed 
out. 

It  is  a  good  plan  to  wash  the  eye  out,  once  or  twice  a  day  only,  with  a  1  per 
cent,  solution  of  silver  nitrate. 

Gonococcal  Conjunctivitis  of  the  New-Born. 

The  eyes  are  affected  during  delivery,  and  the  incubation  period  is  two  to 
three  days.  Infantile  conjunctivitis  does  not  run  such  a  severe  course  as  the  adult 
form,  and  the  cornea  is  not  so  frequently  implicated.  Provided  treatment  is 
commenced  early,  the  prognosis  is  good,  but,  if  delayed,  there  is  always  the  risk  that 
the  infant  may  be  permanently  blind.  The  eyes  should  be  washed  out  every 
half  hour  with  a  weak  solution  of  potassium  permanganate,  and  once  or  twice  a 
day  with  a  1  per  cent,  solution  of  silver  nitrate. 

Prophylaxis  should  play  a  greater  role  here  than  almost  anywhere  else,  since 
attention  to  the  eyes  of  any  new-born  infant  will  prevent  its  developing  gonococcal 
conjunctivitis,  provided,  of  course,  the  mother  is  instructed  re  towels,  etc.  Directly 
afterbirth,  the  eyes  should  first  be  wiped  with  dry  wool,  and  then  with  wool  dipped 
in  a  weak  solution  of  potassium  permanganate.  The  eyes  are  then  opened  and 
two  or  three  drops  of  a  1  per  cent,  solution  of  silver  nitrate  are  dropped  in. 

Iritis. 

As  to  whether  the  so-called  rheumatic  iritis,  which  so  often  accompanies  pains 
in  the  muscles  and  joints  during  an  attack  of  gonorrhoea,  is  due  to  the  gonococcus  or  to 
its  toxine,  no  one  is  yet  absolutely  certain.  In  no  case  of  iritis  or  iridocyclitis  have 
,  gonococci  ever  been  found  in  the  anterior  chamber.  That  an  examination  has  not 
so  far  yielded  positive  results,  is  far  from  being  conclusive  proof  that  the  iritis  is 
not  of  metastatic  origin,  since,  even  in  undoubted  cases  of  streptococcic  and  pneumo- 
coccic  iritis,  it  is  not  always  possible  to  find  the  organism  in  the  aqueous  humour. 

In  favour  of  gonococcal  iritis  being  of  toxic  origin,  is  the  fact  that  the  iritis 
is  usually  bilateral,  and  that  injudicious  use  of  vaccines  may  produce  it.     Moreover, 


I 


GOXORRHOEAL   DISEASES   OF   THE    EYES.  423 

the  iritis  is  more  often  accompanied  by  rheumatic  pains — which  are  of  toxic 
origin — tlian  by  metastatic  arthritis.  The  iritis  is  very  liable  to  recur,  and  it 
usually  runs  an  innocent  course. 

Although  gonotoxic  iritis  is  almost  always  bilateral,  both  eyes  are  not  always 
affected  at  the  same  time,  and  recurrences  frequently  affect  each  eye  alternately. 
In  nearly  all  cases,  the  patient  has  a  chronic  prostato-urethritis,  although  all  signs 
of  a  focus  in  this  region  may  have  vanished  years  ago.  Therefore,  in  treating 
gonotoxic  iritis,  it  is  imperative  to  pay  particular  attention  to  the  prostate  gland, 
if  it  be  wished  to  avoid  a  recurrence.  So  far  as  the  eye  itself  is  concerned,  atropine 
must  be  used  to  prevent  synechiae,  which  very  readily  develop.  Vaccines  are 
also  of  value,  but  must  be  used  with  caution,  since  their  toxic  action  may  at  first 
materially  aggravate  the  eye  condition.  This  fact  again  suggests  a  gonotoxic 
origin  for  this  form  of  iritis,  therefore,  if  vaccines  are  going  to  be  used,  sensitised 
ones  should  be  injected  for  preference,  since  the  endotoxines  therein  are  neutralised 
beforehand 

In  cases  in  which  an  hypopyon  results,  it  is  sometimes  necessary  to  tap  the 
anterior  chamber. 

Other  forms  of  gonorrhoeal  eye  lesions  are  simply  pathological  curiosities,  and 
it  is  extremely  doubtful  whether  any  others  really  exist. 


CHAPTER  XXXVII. 
GONOCOCCAL  RASHES. 

The  known  gonococcal  rashes  are  five  in  number  ;  only  one  is  due  to  the 
organism  itself .  the  other  four  being  due  to  its  toxine.  The  rashes  are:  (1)  gonococcal 
ulcer  and  abscess  ;  (2)  toxic  er}i;hema  ;  (3)  toxic  urticaria  ;  (i)  toxic  haemorrhagic 
and  bullous  dermatitis  ;    (5)  toxic  hyperkeratosis. 

Ulcus  Blennorrhagicum. 

Although  many  of  the  ulcers  which  appear  during  a  gonococcal  infection 
are  doubtless  of  a  secondary  nature,  some  are  certainly  due  to  the  gonococcus 
itself.  To  prove  this,  it  is  not  only  necessary  to  demonstrate  the  gonococci 
in  fihns,  since  they  might  only  have  been  unplanted  upon  the  surface,  but  also, 
on  cleaning  the  surface,  it  is  necessary  to  grow  pure  colonies  of  the  organism 
therefrom.  Chnically,  it  is  impossible  to  differentiate  the  ulcers  caused  by  a 
secondary  infection  from  those  caused  by  the  gonococcus,  and  these  ulcers  are 
commonly  mistaken  for  soft  sores. 

Vlcera  blennorrhagica  are  very  much  more  common  in  women  than  in  men. 
They  may  affect  any  part  of  the  genitals,  the  perineum,  the  skin  around  the  anus, 
and  the  adductor  region  of  the  thighs.  Big  ulcers,  varying  from  13  cm.  in 
diameter  are  very  rare,  and  so  are  serpiginous  ulcers,  but  they  do  occur,  and  they 
are  very  difficult  to  cure.  The  commonest  ulcers  are  small,  and  vary  from  the 
size  of  a  pin's  head  to  that  of  a  pea.  The  lesion  is  usually  crateriform,  i.e.,  the 
edges  are  raised,  heaped  up,  and  swollen.  The  edges  are  not  undermined,  and  the 
surrounding  inflammation  is  not  so  marked  as  it  is  in  Vlcera  niollia. 

The  gonococcal  abscesses  are  usually  the  terminal  ends  of  paraurethral  canals, 
which  have  not  perforated  the  surface,  but  true  gonococcal  abscesses  may  be  met 
with,  and  these  are  always  secondary  to  a  lymphangitis,  and  they  occur  most 
frequently  on  the  dorsum  of  the  penis. 

A  few  cases  of  metastatic  abscesses  have  been  described,  but  lesions  so  rare 
are  nothing  more  nor  less  than  .pathological  curiosities. 


Plate  41. — Keratodermia  Blbnnorrhauica. 


'^ 


Facing  p.  424. 


Platb  41. 


r;il    i;i  ^  ,  -iti'v    .iiu>    i,-;    due   tO    thp 

i3)  toxicurtu 
ic  li>'peikeratosi!r. 

'LESNORRHAGICim. 
>  hic-h   appear  di; 


iused   by 

':  era  are 


ii^i/'h  'nor?*  C'^rti) 


round  t; 


*jt  .-'.i 


Plate  41. 


gonococcal  rashes.  425 

Toxic  Rashes. 

Toxic  rashes,  though  seldom  described,  are  quite  frequently  to  be  met  with, 
if  looked  for.  Winkelried  Williams,^  in  a  recent  article  on  Keratodennia  blennor- 
rhagica,  stated  that,  on  searching  the  literature,  he  could  fmd  only  fifteen  recorded 
cases.  At  the  London  Lock  Hospital  we  get  about  three  cases  per  annum,  and  the 
numbers  would  doubtless  be  very  much  greater,  if  we  examined  the  feet  of  every 
patient  suffering  from  gonorrhoeal  rheumatism  and  arthritis.  The  toxic  erythemata 
are  usually  brushed  aside  at  once,  as  being  copaiba  rashes,  even  if  it  be  known 
that  the  patient  has  not  taken  any  medicine. 

I  have  seen  gonotoxic  erythemata  which  could  not  be  distinguished  from  a 
copaiba  rash,  and  the  similarity  of  some  cases  to  scarlet  fever  and  measles  was 
very  close.  Conjunctivitis  is  not  at  all  an  uncommon  gonotoxic  symptom,  and 
when  it  accompanies  a  discrete  macular  rash,  a  hasty  diagnosis  of  measles  may  be 
very  easily  made.  Some  of  the  scarlatiniform  rashes  may  be  accompanied  by  a 
sore  throat.  Many  of  the  rashes  are  ushered  in  with  fever,  and  joint  pains  are 
not  at  all  uncommon.  True  Erythema  nodosum  may  undoubtedly  be  met  with  as 
a  gonotoxic  rash.  I  remember  one  case  very  well,  as  the  patient  suffered  also 
from  polyarticular  arthritis,  and  died  of  gonococcal  endocarditis.  Microscopic 
sections  of  the  cardiac  valves  revealed  masses  of  Gram  negative  diplococci,  and 
pure  cultures  of  gonococci  were  obtained,  post-mortem,  from  the  heart's  blood 
and,  during  life,  from  a  venepuncture. 

Urticarial,  haemorrhagic,  and  bullous  exanthemata  are  rare,  and  only  a  very 
few  cases  have  been  described.  I  have  seen  purpura  develop  in  severe  cases  of 
polyarticular  arthritis,  but  I  have  never  seen  a  case  of  tru.e  urticaria  or  pemphigus. 

Perhaps  the  most  interesting,  because  the  most  distinctive,  gonotoxic  rash, 
is  the  toxic  hyperkeratosis,  or,  as  it  is  more  commonly  called,  Keratodermia  hlennor- 
rhagica  (Plate  41).  The  patient  from  whom  this  picture  was  made,  was 
suffering  from  his  first  attack  of  polyarthritis.  The  rash  had  taken  only  four  months 
to  develop.  The  other  leg  was  in  a  similar  condition  ;  he  also  had  lesions  on  both 
hands  and  arms,  and  the  typical  Balanitis  circinata. 

The  lesions  are  primarily  vesicles  ;  these  quickly  become  pustules,  and  then 
the  wall  of  the  pustule  becomes  keratinised.  Several  lesions  may  coalesce,  or  they 
may  develop  singly.  Half-a-dozen  lesions  may  appear  on  the  big  toes,  and  the 
condition  may  not  develop  further  ;  hence  it  can  be  readily  understood  that  several 
cases  are  overlooked,  as  a  slight  eruption  of  this  sort  is  by  far  the  most  connnon. 
After  attacking  the  dorsimi  of  the  big  toe,  the  lesions  extend  inwardly,  and  ultimately 
reach  the  sole.  If  the  lesions  increase  in  size,  they  do  so  by  adding  on  successive 
layers  of  keratin,  so  that  it  ultimately  resembles  a  limpet  shell. 


•126  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   GONORRHOEA. 

In  the  severe  cases,  any  part  of  the  bod)'  may  be  affected,  and,  I  may  say, 
that  in  every  case  I  have  seen,  mild  or  severe,  the  patient  has  always  had  a  balanitis. 

Discrete  circular  lesions  fir.st  make  their  appearance  on  the  glans  penis,  corona, 
and  under-surface  of  the  prepuce.  As  the  surfaces  continually  rub  together,  the 
epithelium  in  between  the  areas  soon  becomes  white,  heaped  up,  and  then  entirely 
denuded,  so  that  the  true  circinate  areas  can  only  be  seen  at  the  periphery.  These 
circinate  patches  naturally  never  become  keratinised,  but  true  keratodermia  may 
affect  the  skin  of  the  penis.  When  the  horny  process  is  removed,  no  ulcer  is  exposed, 
but  simply  a  denuded  epithelium.  Although  the  patient  just  referred  to,  from 
whom  the  painting  illustrating  this  chapter  was  made,  was  suffering  from  his  first 
attack  of  polyarthritis,  it  is  more  usual  for  the  keratodermia  to  develop  during 
the  second  or  some  subsequent  attack.  Another  interesting  feature  of  this  condition 
is,  that  the  patients  usually  have  marked  hyperidrosis,  and  this  probably  plays 
a  large  part  in  the  causation  of  the  horny  excrescences.  The  lesions  have  been 
very  carefully  examined  for  gonococci,  but  always  without  success  ;  therefore,  I 
think  it  may  be  assumed  that  Keratodermia  blennorrkagica  is  a  toxic  manife.station. 

Treatment  consists  in  merely  scaling  off  the  scales,  and  in  giving  vaccines, 
by  which  means  the  condition  is  very  rapidly  cured. 

The  case  from  which  the  painting  was  made,  ran  a  course,  which  I  had  never 
seen,  or  heard  described  before.  Localised  blue  congested  patches  developed  in 
the  skin  at  the  base  of  all  the  finger  and  toe  nails.  The  congestion  gradually  spread 
backwards  as  far  as  the  metacarpo-  and  metatarso-phalangeal  joints  respectively, 
the  sweUing  then  subsided  and  gave  way  to  horny  bands,  which  appeared  to  con- 
strict the  affected  areas.  To  the  proximal  side  of  the  congested  digits,  a  skin  lesion 
developed,  which  was  absolutely  indistinguishable  from  Psoriasis  vulgaris.  The 
psoriasiform  rash  on  the  feet  spread  as  far  as  the  ankles,  and  on  the  hands  to  above 
the  wrists.  Oddly  enough  both  elbows  and  knees  became  covered  with  psoriasiform 
lesions,  and  even  the  nails  developed  the  ridges  and  punctate  depressions,  which 
are  so  commonly  to  be  seen  in  cases  of  psoriasis. 

For  the  opportunity  of  studying  this  unique  case,  I  am  indebted  to  Mr.  Lane 
and  Mr.  Gibbs,  under  whose  care  the  case  was. 

'  Wiiikelreid  Williams  (1914),  •'  Brit.  Med.  Journ.,"  ii,  627. 

PAPERS  CONSULTED. 

Buschke  (1912),  "  Archiv.  f.  Derm.  u.  Syphilis,"  cxiii,  22.3. 

Arniug  u.  Meyer-Delius  (1911),  "  Archiv.  f.  Derm.  u.  SyiA.,"  cviii,  1. 


CHAPTER   XXXVIII. 
GONORRHOEA  IN  WOMEN. 

Gonorrhoea  in  women  is,  as  is  also  the  case  with  syphilis,  the  greatest  curse 
of  the  disease.  A  man  always  contracts  a  urethritis,  and  knows  at  once  when  he 
is  infected,  and  it  is  his  own  fault  if  he  does  not  seek  instant  advice.  Not  so  with  a 
woman.  The  genital  organs  may  be  the  first  attacked,  or,  if  the  disease  begins 
in  the  urethia,  the  symptoms  may  be  so  slight,  and  the  trouble  may  spread  to  the 
genital  tract  so  quickly,  and,  even  having  affected  that,  the  symptoms  may  not  be 
sufficiently  severe  to  necessitate  her  taking  advice.  As  a  rule,  a  woman  knows 
when  she  is  infected  ;  at  least  she  knows  there  is  something  wrong,  although  she 
may  be  in  ignorance  of  the  cause,  so  that  she  is  usually  to  blame  for  not  seeking 
medical  opinion.  Considering  how  widespread  gonorrhoea  and  sj'philis  must  be 
in  women,  it  is  odd  what  a  very  small  percentage  of  medical  practice  outside  the 
hospitals,  and  even  in  hospital  practice,  is  taken  up  by  women. 

Where  do  women  go  for  their  treatment  ?  The  answer  is,  that  thev  have  none, 
at  any  rate  not  until  the  setting  in  of  a  compUcation  demands  surgical  interference. 
The  importance  of  the  fact  that  women  do  not,  generally  speaking,  seek  advice 
during  the  acute  and  the  most  infectious  period,  cannot  be  over  estimated,  and 
it  is  a  point  which  shoufd  be  most  seriously  considered  by  any  committee  formed 
to  deal  with  the  extirpation  of  venereal  diseases.  It  is  highly  probable  that 
druggists  and  charlatans  are  more  frequently  consulted  by  women  than  by  men. 
The  former  could  very  easily  be  dealt  with,  but  the  latter  unfortunately  not  so. 
Women  who  are  the  subjects  of  gonorrhoea  are  further  placed  at  a  greater  disadvan- 
tage than  men,  in  that  menstruation  stops  the  treatment  and  aggravates  the  disease. 
Moreover,  once  the  cervix  has  become  affected,  the  disease  is  far  more  difficult  to 
cure  than  when  the  prostate  in  men  is  involved.  Therefore,  in  no  disease  is  an  early 
diagnosis  more  to  be  wished  for  than  in  gonorrhoea  in  women.  The  gonococcus  is 
also  a  greater  cause  of  sterility  in  women  than  it  is  in  men,  but,  oddly  enough,  it 
practically  never  causes  sexual  neurasthenia  in  women.  Men  can  contract 
gonorrhoea  from  sexual  connection  only,  and  this  is  the  most  frequent  source  of 


428  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   GONORRHOEA. 

infection  in  women  ;  but  it  must  be  remembered  that,  in  the  latter,  there  is  another 
source  of  infection,  which  is  too  frequently  overlooked.  Many  women  have  the 
habit  of  wiping  themselves,  after  micturition,  with  any  towel  that  may  be  handy. 
I  have  known  of  four  cases  in  which  virgins  contracted  gonorrhoea  in  this  wa}'^  at 
ladies'  clubs  in  London,  and  I  also  know  of  a  family  in  which  the  mother  and  three 
daughters  all  contracted  gonorrhoea,  from  presumably  using  the  same  bath  towel. 

In  most  cases  of  gonorrhoea  in  women,  the  urethra  is  the  site  of  infection.  The 
disease  then  spreads  to  Bartholin's  glands,  and  from  here,  via  the  vagina,  to  the 
cervix.  The  disease  may  remain  localised  in  the  cervix,  or  it  may  spread  into  the 
uterus,  along  the  Fallopian  tubes,  into  the  general  peritoneal  cavity. 

Although  a  true  gonococcal  vaginitis  is  common  in  young  girls,  it  is  not  often 
met  with  in  adults.  In  adults  it  is  more  likely  to  occur  in  those  patients  who  have 
had  least  sexual  connection. 

Complications  of  the  urinary  tract  are  rarer  in  women  than  in  men.  Gonococcal 
proctitis  is  very  much  more  common,  and  other  complications,  such  as  arthritis,  etc., 
affect  both  sexes  alike.  In  virgins,  and  in  recently  married  women,  in  whom  the 
disease  is  more  likely  to  remain  for  some  time  in  the  vulva  without  spreading,  great 
care  should  be  taken  not  to  insert  any  instrument  into  the  vagina,  as  such  a  pro- 
cedure is  sometimes  a  source  of  infection  of  a  previously  healthy  cervix.  In  women 
who  have  been  married  some  time,  the  cervix  is  apt  to  be  the  initial  site  of  the 
infection.     In  them,  vaginal  douching  can  be  started  straight  away. 

There  are  several  reasons  why  colpitis  should  be  less  common  in  the  sexually 
matured  than  in  virgins.  In  the  former,  the  mucous  membrane  is  not  so 
delicate,  as  the  superficial  layers  of  the  epithelium  make  a  more  or  less  satis- 
factory attempt  to  form  a  horny  layer.  The  adult  vagina  contains  organisms  which 
are  not  met  with  in  the  vagina  of  young  maidens,  and  the  gonococcus,  as  has  been 
frequently  pointed  out  before,  vdW  not  live  in  symbiosis  with  other  bacteria. 
Finally,  the  mucous  membrane  of  the  adult  vagina  secretes  a  mucinous  substance, 
in  which  the  gonococcus  cannot  flourish,  while  the  vagina]  mucous  membrane  of 
young  girls  has  no  secretion. 

Urethritis  in  the  female  tends  to  heal  very  quickly  by  itself,  hence  it  can  be 
easily  reinfected.  It  is  important  to  remember  this,  since,  if  a  woman  has  .symptoms 
of  a  urethritis,  one  is  apt  to  assume  that  she  has  just  been  infected,  while  it  is  by 
no  means  a  rare  occurrence  for  the  cervix  to  be  affected  first  and  the  urethra  after- 
wards, by  a  spread  of  the  organism  from  the  cervix  to  the  urethra,  via  the  vagina. 

Bartholinitis  is  an  extraordinarily  chronic  complication,  and  it  may  not  only 
give  rise  to  an  auto-reinfection  of  the  urethra  and  cervix,  but  also  it  is  a  frequent 
source  of  infection  of  a  second  party. 


GONORRHOEA    IN   WOMEN.  429 

The  ^nllvo -vaginitis  of  children  is  caused  most  frequently  by  the  gonococcus, 
and  it  is  usually  contracted  from  dirty  sponges  and  linen.  The  condition  is  very 
infectious,  and  may  become  almost  epidemic — i.e.,  in  a  children's  ward,  if  there  is 
one  case  of  gonococcal  vulvo-vaginitis,  unless  the  very  greatest  care  be  taken,  every 
female  child  in  the  ward  may  be  infected. 

The  inflammatory  process  always  involves  the  urethra  and  lower  portion  of 
the  vagina. 

Vulvo-vaginitis  may  also  affect  new-born  infants  and  maidens.  The  former 
infection  can  occur  during  birth,  or  a  few  weeks  later.  The  latter  infection  is  of 
importance  from  the  forensic  point  of  view. 

Vulvo-vaginitis  of  children  is  extremely  painful,  and  the  secretion  of  pus  is 
usually  profuse.  The  pus  stains  the  linen  and  makes  it  stiff,  and  this  is  usually 
the  first  indication  that  anything  is  wrong,  then  the  pain  on  passing  water,  etc., 
is  noticed. 

On  examination,  the  inflammation  is  found  to  have  involved  the  labia,  the 
clitoris,  the  hymen,  the  vestibule,  the  urethra  and  the  vagina.  These  structiires 
are  red,  swollen,  and  covered  with  pus  ;  and,  owing  to  the  irritation  of  the  pus,  an 
intertrigo  in  the  genito-criiral  folds  is  the  rule.  The  vestibule  is  often  covered  with 
small  ulcers.  The  hymen  is  pushed  forwards,  owing  to  the  quantity  of  pus  that 
collects  behind  it.  The  inflammation  of  the  labia  and  the  intertrigo  are  caused, 
not  by  the  gonococcus,  but  by  the  irritative  nature  of  the  pus,  which  comes  from 
the  vagina.  The  acute  stage  of  vulvo-vaginitis  is  rather  a  long  one,  and  the  con- 
dition is  rather  obstinate  to  treatment.  The  acute  stage  ultimately  passes  into 
the  chronic  stage,  and  it  is  in  this  stage  that  spontaneous  cure  ultimately  ensues. 
Spontaneous  cure  will  take  place,  whether  the  case  is  treated  or  not,  but  the  disease 
may  persist  for  a  very  long  time  before  this  happens.  Fortunately,  cervicitis  and 
Bartholinitis  do  not  complicate  viilvo-vaginitis. 

In  adults,  one  does  not  speak  of  vulvo-vaginitis,  owing  to  the  fact  that  the 
vagina  is  so  rarely  affected,  but  otherwise  there  is  practically  no  difference  between 
the  two  conditions.  Vulvitis  occurs  in  adults ;  it  is  an  inflammation  of  the 
vestibulum  and  of  Bartholin's  glands,  with  sometimes  ulceration. 

The  gonococcal  urethritis  in  women  is  of  quite  minor  importance  compared 
with  that  in  man,  but  it  may  be  complicated  by  a  paraurethritis.  There  may  be 
one  or  more  canals,  and  the  openings  are  just  external  to  the  urethral  orifice.  A 
paraurethritis  does  not  give  rise  to  symptoms,  and  it  is,  as  a  ride,  only  diagnosed 
by  accident,  when  the  secretion  is  pressed  out  of  the  urethra,  by  the  finger  in  the 
vagina.  These  paraurethral  canals  are  probably  congenital,  and  possibly  the  em- 
bryonic remains  of  Skene's  tubules.     As  a  rule  they  are  easily  closed  by  electrolysis. 


■430  THE   BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   GONORRHOEA. 

When  Bartholin's  gland  becomes  afEected,  and  not  infrequently  both  are 
involved  at  the  same  time,  the  patient  complains  of  acute  pain  on  movement.  On 
examination  in  the  early  cases,  if  pus  has  formed  in  the  glands,  it  can  usually  be 
pressed  out,  but  later  the  duct  and  orifice  become  closed.  So  long  as  the  pus  can 
find  exit,  it  gets  expressed  at  almost  every  movement  on  the  part  of  the  patient, 
and  the  swelling  does  not  attain  to  a  great  size.  The  pain  is  naturally  acutest 
when  the  swelling  is  greatest,  therefore — when  the  only  bearable  position  for  the 
patient  is  to  lie  on  her  back  with  the  legs  wide  apart — the  diagnosis  of  an  abscess 
in  Bartholin's  gland  may  be  made.  Once  an  abscess  has  formed,  the  chances  are 
that  the  lining  membrane  of  the  gland  has  been  destroyed.  Consequent!}',  when 
the  pus  has  been  evacuated  and  the  abscess  healed,  a  recurrence  is  unlikely  to 
ensue. 

When  Bartholin's  gland  merely  becomes  inflamed,  the  inflammation  passes  in 
time  from  the  acute  to  the  chronic  form  ;  and,  once  it  is  chronically  inflamed, 
frequently  recurring  retention  cysts  are  liable  to  arise,  or  suppuration  may  at  any 
time  occur,  due  to  a  secondary  infection. 

Owing  to  there  being  gonococci  ever  present  in  the  chronically  inflamed  gland, 
it  can  be  easily  understood  what  a  great  source  of  infection  a  woman  is  likely  to  be  ; 
and  as  a  chronic  Bartholonitis  runs  a  symptomless  course,  except  when  retention 
cysts  form,  a  woman  may  be  quite  unaware  that  she  is  infectious.  As  already 
stated,  a  true  gonococcal  vaginitis  is  most  often  seen  in  children,  but  it  should  not 
be  forgotten  that  a  gonococcal  vaginitis  is  far  from  being  uncommon  in  pregnant 
women.  This  is  due  to  the  fact  that  the  mucous  membrane  is  swollen  and  softer, 
and  possibly  its  secretion  is  less  acid.  Anyhow,  the  gonococci  can  flourish  in  it. 
Gonococcal  vaginitis  is  also  met  with  in  women  who  have  had  the  uterus  and 
ovaries  removed.  Castration  causes  shrinkage  of  the  vaginal  mucous  membrane, 
reduces  the  number  of  layers  of  epithelial  cells,  diminishes  the  secretion,  and  in 
this  way  the  gonococci  are  more  readily  able  to  penetrate  into  the  connective  tissue 
beneath. 

When  the  gonococci  reach  the  cervix,  in  women  who  have  had  children,  they 
readily  gain  access  to  the  uterus  ;  but  in  all  cases  of  cervicitis,  whether  in  women 
who  have  had  children,  or  in  those  who  have  not,  the  organisms  quickly  spread  into 
the  sub-epithelial  tissue,  and  this  is  the  reason  why  cervicitis  is  so  difiicult  to  cure. 
The  aflected  cervdx  is  usually  somew^hat  oedematous,  and  there  is  always  a  purulent 
or  a  mucous  discharge  from  the  external  os.  As  a  rule,  a  cervicitis  gives  rise  to 
no  symptoms,  but  sometimes,  during  the  menstrual  periods,  owing  to  the  con- 
striction of  the  internal  os  and  the  canal  which  may  be  caused  by  chronic  inflam 
mation,  a  patient  may  complain  of  dysmennorrhoea. 


GONORRHOEA   IN   WOMEN.  431 

The  constant  discharge  from  the  external  os  is  very  liable  to  cause  an  erosion. 

It  is  practically  impossible  to  say  when  a  cervicitis  becomes  an  endometritis, 
but,  from  the  extraordinary  resistance  to  treatment  of  almost  every  case  of  so- 
called  cervicitis,  one  would  probably  not  be  far  wrong  in  stating  that  endometritis 
more  often  accompanies  a  cervicitis,  than  that  a  cervicitis  exists  alone.  Once  the 
organisms  have  gained  entrance  to  the  uterus,  they  rapidly  spread  over  the  surface 
and  under  the  mucous  membrane.  The  ease  with  which  the  gonococci  invade 
the  subepithelial  tiss\;e  is  doubtless  partly  due  to  the  changes  the  epithelium 
undergoes  at  each  menstrual  period,  and  to  the  increased  vascularisation  of  the 
organ  at  this  time. 

The  utenis,  in  acute  endometritis,  is  very  painful  on  j)ressure,  and  the  patient 
cannot  endure  sexual  connection.  General  symptoms  are  usually  severe,  and  the 
patient  nearly  always  has  to  take  to  her  bed. 

The  acute  stage  ultimately  runs  into  the  chronic,  and  it  is  in  this  stage  that 
the  main  symptoms  are  complained  of.  There  are  three  regular  symptoms  :  (1) 
dysmennorrhoea  ;    (2)  menorrhagia  ;    (3)  metrorrhagia. 

Unfortunately,  those  symptoms  may  persist,  even  after  all  the  gonococci  have 
vanished,  probably  because  a  secondary  infection  takes  the  place  of  the  gonococci, 
and  maintains  the  chronic  inflammatory  process. 

Gonococcal  endometritis  is  a  frequent  cause  of  abortion,  and  naturally  com- 
plicates and  aggravates  the  after- results  thereof.  From  the  uterus,  the  gonococci 
travel  to  the  Fallopian  tubes,  and  as  the  organisms  in  most  cases  come  from  all 
over  the  uterus,  a  bilateral  salpingitis  is  much  more  commonly  met  with  than  a 
unilateral  one. 

The  tubes  swell,  become  oedamatous,  and  often  the  lumen  is  obliterated.  The 
pus  formed  at  first  flows  into  the  utenis,  but  it  may  easily  get  pent  up,  and  so 
produce  an  abscess.  As  in  all  gonococcal  affections,  abscess  formation  is  by  no 
means  the  usual  sequence  of  events,  it  being  far  more  common  for  the  acute  inflam- 
mation to  subside  gradually  into  chronic  inflammation.  A  chronic  salpingitis 
runs  a  very  similar  course  to  a  chronic  Bartholinitis,  that  is  to  say,  the  openings 
become  periodically  blocked,  the  secretion  can  find  no  exit,  and  a  retention  cyst 
forms — a  hydrosalpinx.  A  patient  with  salpingitis  usually  has  endometritis  as 
well,  hence  the  symptoms  are  very  much  the  same,  but  in  the  former,  pain  is  com- 
plained of  in  the  lateral  portions  of  the  abdomen.  When  occurring  on  the  right 
side  only,  the  pain  is  frequently  mistaken  for  appendicitis. 

A  certain  diagnosis  of  salpingitis  can  only  be  made  by  a  thorough  digital  and 
bimanual  examination. 

Owing  to  the  adhesions  to  which  a  chronically  inflamed  Fallopian  tube  is  liable 
)  2  E 


■132  THE    BIOLOGY,    CLINICAL    ASPECT   AND    TREATMENT   OF   GONORRHOEA. 

to  give  rise,  patients  frequently  have  varied  abdominal  and  pelvic  pains,  some  of 
which  suggest  bowel  trouble,  others  bladder  trouble,  and  so  forth. 

Owing  to  the  patent  external  ostium  of  the  Fallopian  tube,  the  gonococci 
can  reach  both  the  ovary  and  the  general  peritoneal  cavity.  A  corjDus  luteum 
abscess  is  not  infrequently  of  gonococcal  origin.  Pelvic  gonorrhoea,  a  name  which 
may  well  be  given  to  a  gonococcal  infection  of  the  organs  just  mentioned,  almost 
invariably  produces  chronic  invalidism.  The  patient  has  no  regular  symptoms, 
perhaps  never  has  had  them,  but  complains  of  vague  pains,  and  always  feels  ill  ; 
she  is  often  anaemic,  and  is  usually  constipated.  Unfortunately,  it  is  in  such  a 
condition  that  the  patient  for  the  first  time  seeks  advice,  and  although  one  knows 
that  the  gonococcus  is  at  the  bottom  of  the  whole  trouble,  it  is  difficult  to  explain 
the  situation  to  the  patient,  as  in  many  cases  the  infection  occurred  many  years 
back.  Hence  pelvic  gonorrhoea  is  better  treated  by  a  gynaecologist  than  by 
a  venereal  specialist,  and,  moreover,  an  operation  may  at  any  fiiture  time  be 
required. 

Pelvic  gonorrhoea  is  a  frequent  cause  of  functional  neuroses  in  women,  but, 
oddly  enough,  one  seldom  sees  a  condition  exactly  analogous  to  the  sexual  neuras- 
thenia, so  common  nowadays  in  men. 

Treatment. — The  general  treatment  should  be  the  same  as  that  advised  for 
men.  In  the  acute  stage,  the  patient  should  be  kept  in  bed  when  possible.  The 
greatest  attention  must  be  paid  to  the  bowels,  and  urinary  antiseptics  inter- 
nally may  be  prescribed,  such  as  sandalwood  oil,  urotropin,  salicylic  acid,  or 
cystopurin. 

Vaccines  from  the  very  commencement  are  useful,  as  they  increase  the 
patient's  natural  protective  power,  and  they  no  doubt  check  the  spread  of  the 
disease. 

In  chronic  gonorrhoea,  especially  in  pelvic  gonorrhoea,  vaccines  may  be  the 
only  treatment  that  exerts  any  influence  oil  the  disease — indeed,  in  some  cases  of 
cervicitis  and  endometritis  I  have  seen  vaccines  cure  the  patient. 

In  acute  urethritis,  the  patient  should  wash  out  the  urethra  twice  a  day  with 

a  1  :  4000  solution  of  potassium  permanganate  or  a  1  :  2000  sohition  of   hegonon. 

In  chronic  urethritis  a  1  :  4000  solution  of  zinc  permanganate,  or  a  1  :  2000  solution 

of  albargin  should  be  used. 

In  cases  of  acute  vuhHtis,  the  \ailva  should  be  frequently   washed  with  an 

antiseptic  solution,  then  well  dried,  and  a  dusting  powder  used,  because,  the  dryer 

the  region,  the  less  able  is  the  gonococcus  to  live  and  multiply.     The  dusting  j)owder 

should  contain  light  magnesium  carbonate,  as  this  salt  absorbs  more  than  two 

and  a-half  times  its  own  weight  of  water. 


GONOREHOEA  IN    WOMEN.  433 

R  Zinc  oxide  . .         . .         . .         . .     gr.  x 

Magnes.  carbon  levis     . .         . .         . .     gr.  xx 

Dermatol.  . .         . .  . .         . .     gr.  xx 

Piilv.  Am}-!!.       . .         . .         . .  ad  3j 

M.  f.  pulv. 

On  no  account  should  the  vagina  be  douched,  for  fear  of  carrying  gonococci 
on  the  tip  of  the  nozzle  of  the  syringe  from  the  vulva  to  the  cervix.  In  cases  of 
vaginitis,  naturally  the  vagina  must  be  douched,  but  the  patient  shoidd  be  warned 
against  using  too  strong  a  solution,  douching  too  often,  or  employing  an  instni- 
ment  which  sprays  with  any  great  force. 

In  the  acute  stage,  a  1  :  4000  solution  of  potassium  permanganate,  or  a  1  :  2000 
solution  of  hegonon  are  the  best  solutions  to  be  employed.  In  the  subacute  or 
chronic,  zinc  permanganate,  albargin,  formalin,  and  lysol  are  the  most  suitable. 
In  chronic  cases  of  vaginitis  and  cer\'icitis,  I  have  found  it  very  useful  to  give  the 
patient  large  doses  of  iodides,  and  to  prescribe  perhydrol  as  a  douche.  The  iodide 
soon  comes  into  contact  with  almost  every  cell  in  the  body,  and  when  it  meets  the 
hydrogen  peroxide,  free  iodine  and  oxygen  are  given  off. 

Under  no  condition  should  the  cervix  be  dilated,  in  a  case  of  cervicitis  or 
endometritis.  Small  superficial  injuries  are  bound  to  result,  and,  if  the  gonococci 
have  not.  already  entered  the  subepithelial  tissue,  they  are  certain  to  do  so  now. 
Instrumentation  of  the  cervix  or  uterus,  in  my  opinion,  aggravates  eveiy  case  of 
gonorrhoea  of  these  organs,  whether  the  case  is  subacute  or  chronic.  Curetting  for 
endometritis  I  have  never  yet  seen  do  any  good. 

Furthermore,  instrumentation  of  the  cervix  or  the  uterus,  even  in  the  chronic 
stage,  is  always  liable  to  start  up  an  acute  salpingitis,  with  the  additional  risk  of  a 
peritonitis  following.  Applications  of  antiseptics  can  only  kill  those  gonococci 
with  which  the  solution  comes  in  contact ;  therefore  dilating  the  cervix  and  painting 
the  surface,  or  the  interior  of  the  uterus,  is  never  going  to  affect  those  organisms 
which  have  already  penetrated  deeply  into  the  connective  and  muscular  tissue. 
These  can  only  be  reached  by  the  blood  stream,  and  as  we  have  no  drug  in  gonorrhoea 
analogous  to  salvarsan  in  syphilis,  we  must  admit  that  chronic  gonorrhoea  in  women 
is  beyond  our  assistance  at  present.  We  have  vaccines  certainly,  but  the  eclatant 
results  which  may  sometimes  be  obtained  with  them  are  far  from  being  universal. 
Some  observers  are  in  favour  of  cauterising  the  cervix  and  uteiiis  in  chronic 
cervicitis  and  endometritis  with  formalin,  iodine,  trichloracetic  acid,  or  silver 
nitrate,  biit  I  am,  personally,  very  sceptical  as  to  the  amount  of  good  it  does. 

Menge  lays  a  great  deal  of  value  on  the  treatment  of  chronic  cervicitis  and 
endometritis  by  cauterisation  with  formalin.     In  his  hands  it  appears  to  have  been 
'  2  E  2 


434  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT    OF   GONORRHOEA. 

successful,  therefore,  in  those  cases  which  have  failed  to  respond  to  vaccines,  one 
may  fall  back  upon  this  as  a  reserve  treatment. 

Menge  uses  formalin  either  undiluted,  or  in  a  50  per  cent,  solution.  He  runs 
wool  round  a  hard  gum  elastic  uterine  sound,  soaks  the  wool  with  the  solution,  and 
swabs  out  the  cavity. 

In  Bartholinitis,  with  abscess  formation,  the  pus  should  be  evacuated  through 
a  small  incision,  and  the  abscess  cavity  washed  out  with  normal  saline  or  a  weak 
antiseptic  solution,  and  then  the  trouble  usually  cures  itself.  In  chronic  Bartho- 
linitis, in  which  cysts  are  continually  forming,  the  onh'  thing  to  do  is  to  remove 
the  sack. 

The  treatment  of  vulvo-vaginitis  in  children  merely  consists  in  washing  out  the 
vagina  with  a  2  per  cent,  solution  of  sUvcr  nitrate,  and  keeping  the  genitals  and 
genito-crural  folds  dry,  to  prevent  the  spread  of  the  dermatitis.  If  the  skin  be 
already  inflamed,  it  is  a  good  plan  to  apply  liquid  paraffin,  to  let  this  dry,  and  then 
to  put  on  a  weak  Lassar's  paste,  which  contains  no  salicylic  acid. 

As  the  child  usually  struggles  when  being  treated,  and  as  the  vaginal  orifice  is 
small,  the  best  way  to  wash  out  the  vagina  is  through  a  narrow  rubber  catheter. 


CHAPTER  XXXIX. 

THE  TREATMENT  OF  GONORRHOEAL  INFECTIONS  BY  VACCINES, 
AND  THE  APPLICATION  OF  THE  COMPLEMENT  FIXATION  TEST 
IN   GONORRHOEA. 

Vaccines  we  owe  to  the  brilliant  work  of  Wright.'  When  they  first  came  into 
use,  the  discoverer  wisely  suggested  that  the  doses  should  be  regulated  by  the 
opsonic  index,  as  the  correct  doses  had  not  been  ascertained.  We  have  since 
learnt  that  the  opsonic  index  is  not  necessary.  This  is  fortunate,  because  in 
gonococcal  infections  it  is  not  only  difficult  to  determine,  but  also  the  results 
obtained  are  very  unsatisfactory. 

AVhy  are  the  results  unsatisfactory  ?  The  opsonic  index  is  supposed  to  be 
a  measure  of  the  protective  capacity  of  the  host,  and  is  estimated  by  the  number 
of  organisms  which  a  certain  number  of  polymorphonuclear  leucocytes  have 
ingested.  In  other  words,  the  opsonic  index  is  the  phagocytic  index.  Although 
phagocytosis  is  regarded  by  many  as  the  premier  protective  mechanism  of  the 
body,  it  is  possible  that  it  may  be  only  of  very  secondary  importance.  In 
gonorrhoea,  I  cannot  help  thinking,  that  the  gonococcus  lives  at  the  expense  of 
the  polymorphonuclear  leucocj^te ;  in  which  case  the  opsonic  index  in  this  disease 
would  certainly  be  untrustworthy.  In  my  opinion,  the  main  protective  substance 
in  the  body  is  the  lipoid-globulin,  which  has  its  origin  in  the  lymphocytes,  and  which 
circulates  in  the  serum.  What  probably  happens  in  bacterial  diseases  is,  that  the 
bacteria  are  killed  by  the  lipoid-globulin,  and  then  are  ingested  by  the  polymorpho- 
nuclears, and  so  are  removed. 

The  polymorphonuclear  leucocyte  is  a  degenerate  cell.  The  polymorphism 
of  the  nucleus  is  a  sign  of  degeneracy,  so  is  the  fact  that  the  nucleus  contains  no 
nucleolus,  and  added  to  this  are  the  feeble  staining  properties  of  the  protoplasm. 
Another  sign  of  degeneracy  is  the  fact,  which  no  one  seems  to  have  observed,  that 
a  polymorphonuclear  leucocyte  cannot  change  ;  in  other  words,  it  cannot  be  the 
starting  point  of  a  new  growth,  innocent  or  malignant,  as  a  Ipnphocyte  or  an 
endothelial  cell  can  be.     Therefore,  one  could  not  expect  it  to  be  more  than  a 


436  THE    BIOLOGY,    CLINICAL   ASPECT    AND    TREATMENT   OF   GONORRHOEA. 

scavenger  of  dead  bacteria,  and  to  be  itself  sometimes  preyed  iipon.  If  it  be  true 
that  the  chief  protective  mechanism  of  the  host  rests  in  the  circulating  lipoid- 
globulin,  which  is  manufactured  by  the  IjTnphocytes,  and  which  kills  the  bacteria 
by  a  process  of  adsorption,  it  woidd  be  better  to  supplant  the  opsonic  index  test 
by  one  which  measured  the  adsorptive  capacity  of  the  patient's  serum.  Although 
it  is  not  necessary  to  regulate  the  dose  of  vaccine  by  estimating  the  adsorptive 
index,  which  is  done  by  the  complement  fixation  test,  this  test  might  be  of  great 
use  in  estimating  the  potency  of  the  various  vaccines. 

With  these  two  \'iews  before  us,  Klein  and  I^  undertook  a  series  of  experi- 
ments in  1912,  and  as  most  of  the  work  is  still  up  to  date,  I  think  it  would  be  best 
to  copy  it  here,  adding  any  information  which  further  experience  has  taught  me. 

The  special  objects  of  the  research  were :  (1)  to  study  the  sermn  in  gonococcal 
infections  (by  the  complement  fixation  test)  in  a  sufficient  number  of  undoubted 
cases  ;  (2)  to  note  what  changes,  if  any,  were  produced  by  vaccine  treatment  in 
the  sera  of  such  cases  ;  (3)  in  this  way  to  use  the  method,  not  so  much  for  diagnosis, 
as  for  gauging  the  progress  of  a  case  under  vaccine  treatment ;  and  (i)  to  deduce, 
from  these  results,  the  indications  for  vaccines,  and  the  best  method  of  employing 
them. 

Details  of  the  Complement  Fixation  Test. 

1.  Complement. — Guinea-pig's  serum,  not  more  than  twenty-four  hours 
old.  Titrated  before  use  with  the  standard  dose  of  corpuscles  and  haemolytic 
serum,  1  in  10,  1  in  20,  1  in  30,  etc.  The  dilution  used  for  the  test  was  three  times 
the  smallest  amount  of  complement  required  to  give  complete  haemolysis  in 
20  minutes. 

2.  Serum  of  Patients. — Inactivated  by  heating  to  56°  C.  for  half-an-hour. 
Diluted  1  in  -5.  Sera  taken  some  days  previously  to  being  tested  were  kept  sealed 
up,  in  the  dark,  at  0°  C.  In  all  cases,  the  serum  was  pipetted  off  from  the  blood 
corpuscles  as  soon  as  possible. 

3.  Antigen. — 24  to  48  hours'  cultures,  on  freshly  prepared  ascites  fluid  or 
pleural  fluid  agar.  (The  melted  agar  was  cooled  to  45°  C,  and  the  fluid  added 
in  the  proportion  of  1  in  5.  The  media  were  incubated  to  ensure  sterility  before 
use.)  The  resulting  growth  was  emulsified  in  normal  saline  containing  0'5  per 
cent,  phenol,  and  the  strength  of  the  emulsion  was  found  by  counting  against  normal 
blood  according  to  Wright's  method. 

Titration  before  use. — This  is  done  by  taking  various  concentrations,  and 
adding  to  them,  in  separate  tubes,  the  standard  dose  of  complement  (previously 
determined,  as  above^,  and  the  standard  dose  of  a  non-gonorrhoeal  serum.     After 


TREATMENT   OF   GONORRHOEAL    INFECTIONS    BY    VACCINES.  437 

incubating  for  one  hour  at  37°  C,  the  sensitised  corpuscles  are  added  +  "5  c.c.  of 
saline.  The  most  concentrated  emulsion  which  permits  complete  haemolysis  to 
occur  is  that  used  for  the  actual  series  of  tests. 

Bacterial  emulsions  have  the  property  of  fixing  complement  to  a  considerable 
degree,  without  the  presence  of  the  corresponding  antibody.  For  example,  the 
following  result,  with  the  gonococcus  emulsion,  is  typical  of  what  was  found : — 

With  emulsion  of  900  million  gonococci  per  c.c.      . .     No  haemolysis. 
,,  ,,  600  „  ,,  . .     Partial  haemolysis. 

,,  ,,  300  ,,  ,,  . .     Complete  haemolysis. 

As  a  rule  300  to  500  million  per  c.c.  are  about  the  limits  between  which  the  strength 
of  the  emulsion  is  adapted  to  the  successful  working  of  the  test.  With  weaker 
emulsions,  positive  results  will  be  still  obtained  with  sera  highly  immunised,  but 
failures  are  the  rule,  with  sera  less  rich  in  antibody. 

We  employed,  altogether,  fifteen  strains  of  gonococci.  The  ideal  procedure 
is  to  make  an  emulsion,  from  a  fresh  2-1  to  -18  hours'  culture,  the  clay  before  each 
series  of  tests.  As  soon  as  the  strain  with  which  we  were  working  began  to  fail 
in  subculture,  a  new  one  was  obtained,  if  possible.  Emulsions,  if  kept  for  further 
use,  were  stored  in  the  dark  at  0°  C.  ;  in  these  conditions  they  appear  to  remain 
little  impaired  for  10  days,  but  slowly  lose  their  power  of  combining  with  the 
specific  antibody.  In  this  respect,  different  strains  vary,  as  one  of  our  emulsions 
retained  its  antigen  properties  for  considerably  longer  than  the  rest. 

4.  Corpuscles.^We  used,  throughout,  sheep's  blood  corpuscles,  thoroughly 
washed,  in  a  5  per  cent,  suspension  in  saline. 

5.  Amboceptor. — The  haemol}i;ic  serum  of  the  rabbit  is  obtained  in  the  dried 
form  in  sealed  tubes.  The  contents  of  each  tube  are  dissolved  at  the  time  of.  use 
in  a  measured  volume  of  distilled  water  and  of  saline,  and  provide  a  strongly 
haemolytic  fluid  (several  times  the  minimum  required).  In  this  way  one  has  a 
potent  haemolytic  serum  of  constant  strength,  with  which  one  is  certain  of  obtaining 
haemolysis,  if  complement  is  present. 

One-tenth  c.c.  each  of  complement,  of  antigen,  and  of  serum  to  be  tested,  is 
taken.  Control  sera  (both  negative  and  positive  controls)  were  also  employed  in 
every  series,  and  used  in  the  same  way — "1  c.c.  of  a  1  in  5  dilution. 

For  each  serum  there  were  two  tubes — one  containing  serum  and  complement ; 
the  other,  serum,  complement,  and  antigen.  The  former  tube  serves  as  the  control, 
and  must  in  every  case  show  haemolysis  at  the  conclusion  of  the  experiment. 

Tube  A,  containing  antigen  and  complement  without  serum,  serves  as  a  control 
for  the  whole  series,  and  it  must  also  show  complete  haemolysis. 


438  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF    GONORRHOEA. 

These  tubes  are  incubated  at  37°  C.  for  one  tour.  To  each  tube  is  then  added 
"1  c.c.  each  of  corpuscles,  and  of  haemolytic  serum,  and  "5  c.c.  saline. 

After  20  minutes  at  37°  C.  the  controls  have,  as  a  rule,  all  haemolysed,  and  the 
results  can  be  read  of?. 

KeMARKS   on   the    above,    AND   ON    THE   INTERPRETATION  OF  THE  KeSULTS. 

The  dilution  of  sera  to  he  tested. — As  the  result  of  preliminary  work  with  the 
complement  fixation  test  in  bacterial  infections,  it  has  been  found  that  the  dilution 
of  1  in  10  (such  as  is  usually  employed  In  the  syphilis  test)  is  too  high.  In  this 
dilution,  only  very  strongly  positive  sera  will  cause  fixation  of  complement.  It 
was  essential,  for  the  object  in  hand,  to  be  able  to  detect  the  presence  of  lesser 
degrees  of  immunity — 1  in  5  was  found  to  be  the  most  suitable  dilution  for  the 
test. 

The  quantitative  test. — It  is  obviously  desirable  to  have  some  means  of  estimating 
differences  in  the  degree  to  which  fixation  of  complement  occurs — (a)  Between 
different  sera  ;  {h)  still  more  between  the  samples  of  one  patient's  serum  obtained 
at  different  stages  in  the  progress  of  the  treatment. 

Klein^  had  previously  noted  the  use  of  two  methods  of  estimating  the  strength 
of  the  positive  reaction  in  Wassermann's  reaction  :  (a)  By  finding  the  amount  of 
complement  adsorbed  ;  (6)  by  finding  the  highest  dilution  of  the  serum  with  which 
a  positive  result  is  obtained. 

Neither  of  these  methods  is  so  easy  to  carry  out  in  the  true  bacterial  tests  as 
in  the  syphilis  reaction,  and  it  was  decided  not  to  attempt  them  in  these  experiments. 

Instead,  recourse  was  had  to  the  following  simple  method.  The  varying 
results  were  indicated  thus  : — 

Complete  fixation  of  complement,  or  no  haemolysis,  as  shown 
by  the  corpuscles  remaining  in  undiminished  bulk  and  the 
fluid  contents  of  the  tube  remaining  perfectly  clear  . .         . .     +  +  + 

Almost  complete  fixation,  or  a  trace  of  haemolysis,  as  shown  by 
the  bulk  of  corpuscles  remaining  undiminished,  but  the  fluid 
being  tinged  with  a  trace  of  haemoglobin      . .         . .         ...         +  + 

Partial    haemolysis,    where    the    total    mass    of    corpuscles    is 

diminished,  but  yet  remains  sufficient  to  form  a  precipitate  + 

Doubtful  result,  where  there  remain  insufficient  corpuscles  to 
form  a  precipitate,  though  their  complete  solution  is  not 
effected  {i.e.,  so  as  to  give  a  clear  solution)     . .         . .         . .  + 


TREATMENT   OF   GONORRHOEAL   INFECTIONS   BY    VACCINES.  439 

"  Control  "  sera. — In  every  series,  at  least  one  known  positive  and  one  known 
negative  serum  were  included.  For  the  latter,  were  tested,  altogether,  from  30  to 
40  sera  of  normal  persons  and  of  patients  suffering  from  diseases  other  than 
gonorrhoea — e.g.,  syphilis.  In  no  single  case  has  any  fixation  of  complement  been 
noted  with  these  sera.  For  positive  sera,  it  was  always  contrived  to  have  available 
a  serum  with  which  a  +  +  +  result  had  already  been  obtained.  (Sera  remain 
active  for  at  least  a  fortmght,  if  kept  undiluted  in  the  dark  at  0°  C.  in  sealed  pipettes.) 
In  addition,  an.  anti-gonococcal  serum  from  Burroughs  and  Wellcome  was  always 
used  (serum  of  a  horse  immunised  by  subcutaneous  injections  of  cultures)  ;  with 
this  serum  a  +  +  +  result  was  obtained  in  dilutions  up  to  1  in  10. 

Antigens  from  different  strains  of  the  gonococcvs — the  relative  advantages  of 
single  and  multiple  antigens. — Amongst  previous  workers  who  have  examined 
gonococcal  infections  by  the  complement  fixation  test,  Teague  and  Torrey* 
found  that  the  serum  of  an  animal  immunised  to  one  strain  of  gonococcus,  may 
fail  to  cause  fixation  of  complement,  in  the  presence  of  an  antigen  obtained  from 
a  different  strain. 

Similarly,  Watabiki,*  having  immunised  rabbits  against  eight  different 
strains  of  the  gonococcus,  found  that  six  sera  gave  a  strong  reaction  with  six  certain 
strains  of  gonococcus,  and  that  two  gave  strong  reactions  with  two  other  certain 
strains  of  gonococcus.  Schwartz  and  McNeil*  also  found  that  various  antigens 
differed  in  their  reaction  with  gonorrhoeal  sera. 

Of  all  the  strains  of  gonococcus  used  in  the  complement  fixation  test,  there 
was  only  one  which  entirely  failed  to  act  as  an  antigen.  The  first  series  of  tests 
was  performed  with  two  separate  antigens  ;  no  difference  was  observed  in  the 
results.  In  passing  from  an  old  to  a  fresh  antigen,  both  were  tested  against  a  known 
+  +  +  serum.  If  the  new  strain  also  gave  a  +  +  +  result,  it  was  accepted  as 
satisfactory,  and  was  used  until  its  subcultures  began  to  fail.  This  method  may 
be  considered  the  best  one  for  counteracting  the  differences  that  may  exist  between 
one  strain  and  another.  The  American  workers,  quoted  above,  concluded  that, 
in  attempting  the  diagnosis  of  gonorrhoeal  infections  by  the  complement  fixation 
test,  the  antigens  used  should  be  extracts  of  several  different  strains. 

This  conclusion  is  not  disputed,  as  regards  diagnosis,  but  these  experiments 
deal  generally  with  cases  in  which  the  diagnosis  was  already  established,  and, 
therefore,  the  complement  fixation  test  was  employed  rather  to  estimate  the 
variations  in  the  antibody  present  in  the  individual  cases  at  different  stages. 

On  practical  grounds  two  criticisms  seem  permissible : — 

(a)  The  different  strains  (as  recommended  by  Teague  and  Torrey) — say,  six 
in  number — must  either  be  combined  to  form  a  single  emulsion,  or  they  must  be 


4-10  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   GONORRHOEA. 

used  separately.  In  the  former  case,  supposing  only  one  of  the  six  is  the  true 
corresponding  antigen  for  the  serum  tested,  the  effect  is  very  much  the  same  as  if 
the  antigen  consisted  of  1  part  effective  antigen,  and  5  parts  wa.ste  products.  In 
the  latter  case,  for  each  serum  tested,  seven  separate  tubes  will  be  required,  and 
the  test  becomes  unwieldy  in  dealing  with  a  series  of  cases. 

(6)  If  the  antigens  employed  are  to  be  from  tolerably  recent  cultures  or  sub- 
cultures (which  has  been  shown  to  be  deskable),  a  great  amount  of  labour,  and 
an  abundant  supply  of  fresh  material  is  required,  to  maintain  several  strains  of 
gonococcus  in  pure  culture. 

The  differences  between  several  strains  of  the  gonococcus,  as  regards  the  fixation 
of  complement  in  the  presence  of  the  specific  amboceptor.  Are  these  differences  related 
to  the  nature  of  the  gonorrhoeal  infection  from  which  the  strain  u-as  isolated  ? — From 
a  mild  to  a  severe  infection,  all  grades  exist.  The  strains  of  gonococci  employed 
were  obtained  from  acute  and  subacute  cases,  not  all  of  the  same  degree  of 
severity.  Some  of  the  strains  were  further  used  as  vaccines.  Differences  of  two 
kinds  were  noted  : — 

(1)  Some  were  more  potent  than  others,  as  antigens  in  the  complement 
fixation  test,  with  the  same  gonorrhoeal  serum. 

(2)  Some  were  more  potent  than  others,  as  vaccines. 

There  is  a  third  difference,  namely,  the  effect  of  the  strains  when  inoculated 
into  an  animal.  Differences  have  been  shown,  both  as  regards  the  toxic  effect 
produced,  and  as  regards  the  degree  to  which  the  formation  of  antibodies  is 
stimvdated  (Watabiki^).  It  is  not  made  clear,  however,  whether  such  differences 
bear  any  definite  relation  to  the  severity  or  mildness  of  the  case  from  which  the 
strains  of  the  organism  were  derived. 

Similarly,  with  regard  to  the  differences  noted  in  these  experiments  under 
headings  (1)  and  (2)  ;  they  do  not  correspond  to  the  severity  or  mildness  of  the 
case  from  which  the  strain  in  question  originated.  A  few  examples  will  make  this 
point  clear.  One  can  single  out  one  strain  of  the  series  which  was  of  marked 
potency  in  both  (1)  and  (2).  This  strain  was  derived,  not  from  a  severe  case,  but 
from  a  case  of  acute  anterior  urethritis,  which  was  cured  in  10  days,  with  potassium 
permanganate  injections  as  the  sole  treatment.  On  the  other  hand,  an  antigen 
prepared  from  a  culture  from  the  heart's  blood  of  a  fatal  case  of  gonococcal  septi- 
caemia was  by  no  means  so  active.  Again,  one  strain  was  grown  from  a  subacute 
case  of  urethritis  of  average  severity  in  a  male  ;  the  culture  was  not  by  any  means 
abundant,  but  was  undoubtedly  the  true  gonococcus.  The  emulsion  of  this  culture 
failed  entirely  to  fix  complement  in  the  presence  of  a  known  -I-  -t-  -H  serum. 

It  appears,  therefore,  that  no  definite  relation  can  be  traced  between  the 


TREATMENT   OF   GONORRHOEAL    INFECTIONS    BY    VACCINES.  441 

nature  of  the  case  from  which  a  strain  of  gonococcus  is  derived,  and  the  properties 
of  this  strain,  as  tested  by  the  complement  fixation  test.  Such  a  conclusion  is  quite 
in  harmony  with  the  known  facts  witli  regard  to  the  relative  virulence  of  strains 
of  the  diphtheria  bacillus,  or  of  the  typhoid  bacillus.  For  example,  strains  of  the 
diphtheria  bacillus,  from  such  a  mild  affection  as  membraneous  rhinitis,  have  been 
shown  to  have  a  marked  virulence,  when  injected  into  guinea-pigs. 

Hence  it  may  be  inferred  that  the  relative  virulence  of  any  given  strain  of  the 
gonococcus  is  not  the  chief  factor  in  determining  the  severity  or  mildness  of  the 
infection.  There  must  be  other  factors,  such,  for  example,  as  the  resistance  of 
the  infected  individual,  the  site  of  entrance  of  the  micro-organism  (cf .  the  different 
streptococcal  diseases  produced  by  the  streptococcus  pyogenes,  according  to  the 
path  by  which  it  finds  an  entrance  into  the  body),  and  the  quantity  of  the  virus 
which  is  implanted  upon  the  host. 

Vaccines. — All  that  has  been  said  of  the  method  of  obtaining  the  cultures, 
making,  and  counting  the  emulsions  for  the  antigen  in  the  complement  fixation 
tests,  applies  to  the  preparation  of  vaccines.  In  fact,  many  of  the  strains  were 
used  for  both  purposes. 

Emulsions  intended  for  use  as  vaccines  were,  however,  autolysed  for  24  hours 
at  37  C°.,  to  kill  the  gonococci.  No  heat  was  employed.  The  gonococcus  rapidly 
autolvses  at  blood  heat,  and  no  living  cocci  remain  at  the  end  of  24  hours. 


The  Three  Methods  of  Vaccine  Treatment  Employed. 

1.  Vaccines  injected  subcutaneoushj ,  in  the  usual  way. — The  initial  doses  were 
5  to  10  million,  then  increasing  to  50  million  or  100  million,  and  occasionally 
200  million  were  used. 

Our  vaccines  were  prepared,  when  possible,  from  the  primary  culture  ;  when  this 
was  not  practicable,  from  the  earliest  subculture  possible.  Generally,  48  hours' 
cultures  were  preferred.  At  the  end  of  24  hours,  the  growth  is  frequently  not  veiy 
copious.  Stock  emulsions  of  high  concentration  (1,000  million  per  c.c.)  were  stored 
in  the  dark  at  0°  C,  for  future  use.  In  this  condition  they  slowly  lose  their  strength, 
but  they  remain  active  for  10  days  or  more,  and  may  retain  much  of  their  original 
properties  even  after  a  month.  Nevertheless,  the  most  recently  made  vaccines 
at  hand  were  always  used,  never  more  than  a  fortnight  old,  for  the  subcutaneous 
method. 

Therapeutic  effects. — Such  vaccines,  I  found,  rarely  failed  to  produce  a  certain 
reaction,  sometunes  a  marked  reaction,  even  in  the  moderate  doses  employed.  I 
should  not  have  been  prepared  to  inject  them  in  the  large  doses  sometimes  advocated. 


442  THE    BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   GONORRHOEA. 

aud  I  am  incliued  to  believe  that  the  stock  vaccines  which  cau  with  inipuuity  be 
employed  in  doses  of  several  thousand  million  must  be  either  old  preparations,  or 
must  be  made  from  strains  attenuated  by  repeated  subculture. 

I  did  not  use  autogenous  vaccines.  In  the  chronic  cases  with  arthritis,  which 
formed  the  bulk  of  the  cases,  such  a  proceeding  was  difHcult,  if  not  impossible. 

In  general,  I  am  of  opinion  that  it  is  far  more  important  in  gonorrhoea  to  use 
a  vaccine  recently  made  from  an  original  culture,  or  first  subculture,  than  to  lay 
great  stress  on  the  vaccine  being  autogenous. 

Two  preparations  on  the  market  were  also  employed  for  subcutaneous  injection, 
namely,  "  Gonargin  "  and  "  Arthigon." 

Tested  by  the  complement  fixation  method,  gonargin  showed  the  presence 
of  antigen,  though  not  to  anything  like  the  extent  to  which  it  was  present  in  the 
freshly  made  emulsions.  Arthigon  had  very  feeble  properties  as  a  vaccine,  and 
in  the  complement  fixation  test  no  definite  result  could  be  obtained,  unless  the 
emulsion  was  so  diluted  as  to  make  the  test  valueless.  The  emulsion  per  se  fixed 
complement  to  an  extraordinary  degree,  so  that  little  use  was  made  of  the 
"  Arthigon  "  preparation  for  treatment,  for  the  above  reasons. 

An  increase  is  produced,  temporarily,  in  the  discharge  in  many  cases,  with 
all  the  ordinary  subcutaneous  vaccines  employed,  and  this  temporary  increase  tends 
to  dmiinish  with  each  succeeding  injection. 

A  negative  phase  almost  invariably  occurs  after  every  subcutaneous  injection, 
and  its  duration  depends  upon  the  dose  used  and  upon  the  interval  which  elapses 
between  successive  doses.  One  case  received  50®  gonargin  on  three  successive 
days,  with  the  result  that  the  complement  fixation  test  did  not  return  to  positive, 
as  it  was  before  the  first  dose  was  given,  for  three  weeks,  during  which  time  the 
discharge  increased,  and  the  epididjTnitis  lighted  up  again. 

If,  then,  vaccines  are  to  be  used  subcutaueously,  or  better  intramuscularly, 
as  by  the  latter  route  the  local  reaction  is  prevented,  only  small  doses  should  be 
employed,  and  longer  intervals  should  be  allowed  between  the  succeeding  injections 
than  are  generally  advised.  The  dose  should  range  from  5  to  10  million,  and  should 
not  be  repeated  for  a  fortnight,  or  even  longer;  then  each  future  interval  can  be 
gradually  shortened,  as  the  duration  of  the  negative  phase  diminishes. 

The  value  of  gonococcal  emulsions  as  vaccine  and  as  antigen  in  the  comjUement 
fixation  test. — An  emulsion  of  gonococci  is  an  "antigen,"  i.e.,  it  contains  the  bacterial 
bodies  and  endotoxines  which,  when  inoculated  into  the  living  organism,  give  rise 
to  the  formation  of  specific  antagonistic  substances,  or  antibodies. 

The  term  antigen,  perhaps  unhappily,  is  also  commonly  used  to  denote  that 
factor  in  the  complement  fixation  test  which  combines  with  the  antibody.     The  term, 


TREATMENT   OF   GONORRHOEAL   INFECTIONS    BY    VACCINES.  443 

ill  both  cases,  is  applied  to  the  same  thing — the  bacterial  emulsion,  but  to  two 
different  eiiects  of  it — one  manifested  in  the  living  organism,  the  other  in  the 
experiment  in  vitro. 

Nevertheless,  it  is  a  probable  inference  that  an  emulsion  of  bacteria  which  has 
a  high  antigen  value  in  the  test,  in  vitro,  will  also  have  a  high  antigen  value,  when 
injected  into  a  living  animal  or  patient. 

Klein  and  I  found  in  practice  that  the  emulsions  which  most  completely  fixed 
complement  (in  the  presence  of  positive  sera),  were  most  likely  to  provide  potent 
vaccines. 

A  curious  phenomenon  encountered,  may  be  briefly  alluded  to  in  this  place. 
A  patient  whose  serum  was  repeatedly  examined,  was  a  man,  A.  K.,  set.  22,  suffering 
from  severe  gonorrhoeal  arthritis  of  many  joints.  His  serum,  at  intervals  of  over 
a  month,  always  gave  a  +  +  +  with  several  antigens,  with  one  exception,  namely, 
the  strain  of  gonococcus  isolated  from  his  own  urethra  after  prostatic  massage. 
With  this  strain  the  fixation  of  complement  was  incomplete  ;  it  was  recorded 
as  ++. 

2.  Intravenous  Injections  of  Vaccine. — Having  ascertained  how  to  obtain  active 
vaccines  for  subcutaneous  injection,  the  next  experiments  were  directed  to  the 
use  of  them  intravenously. 

For  this  purpose,  an  autolysed  emulsion,  containing  originally  1,000  million 
gonococci  per  c.c,  was  used.  It  had  been  kept  in  a  sealed  tube  at  0°  C.  for  more 
than  three  weeks.  On  centrifugalisatioii,  the  amount  of  deposit  was  very  slight. 
A  comparatively  old  emulsion  was  purposely  preferred  to  a  more  recent  one,  as  being 
more  completely  autolysed,  and  as  containing  more  of  the  active  princij^le  in 
solution.  Obviously,  it  might  be  thought  inadvisable  to  inject  intravenously  an 
emulsion  containing  bacterial  bodies,  even  though  dead.  The  supernatant  fluid 
was  pipetted  off,  and  was  ascertained,  by  culture,  to  be  sterile.  It  was  then 
tested  for  complement  fixation,  in  the  presence  of  a  known  +  +  +  serum.  Com- 
pared with  a  recent  emulsion,  which  was  in  use  at  the  time,  it  had  lost  some  of  its 
power,  but  retained  sufficient  to  justify  its  use  as  a  vaccine.  I,  therefore,  started 
to  use  it  in  comparatively  large  doses,  namely,  5  million.  In  diluting  down,  the 
fluid  was  reckoned  as  =  1000 million  per  c.c,  and  the  smaller  doses  were  calculated 
accordingly.  Each  injection  was  given  in  5  oz.  of  saline,  as  by  using  a  large  bulk 
of  fluid  a  more  general  distribution  would  be  achieved. 

Effect  of  injections. — The  above  sterile  fluid,  injected  subcutaneously  in  doses 
of  10  million,  was  followed  by  little  reaction  and  good  therapeutic  effect.  Intra- 
venous injections  in  smaller  doses  produced  no  reaction,  and  the  beneficial  effect 
was  marked,  even  in  doses  of  1  million. 


i-li  THE    BIOLOGY,    CLINICAL    ASPECT    AND    TREATMENT    OF   GONORRHOEA. 

It  is  not  necessary,  or  wise,  to  exceed  a  dose  of  20  million  ;  probably,  even 
with  5  or  10  million,  just  as  good  results  are  obtained.  The  doses  used  were  probably 
too  large.  It  might  be  better  to  start  with  1  million,  and  then  gradually  increase 
by  1  million  weekly.  Contrary  to  what  might  be  expected,  the  negative  phase 
is  negligible  (judged  by  clinical  signs  and  the  serum  reaction),  after  intravenous 
injecton  of  vaccine,  provided  too  big  a  dose  has  not  been  given.  In  this  respect, 
intravenous  vaccines  are  preferable  to  subcutaneous  ones. 

Effect  on  the  jMiiienfs  serum,  as  shown  by  the  fixation  of  complement. — The 
patients  treated  by  the  intravenous  injection  of  vaccine  were  mostly  those  who 
had  given  a  strong  positive  reaction  in  the  complement  fixation  test.  Following 
the  injections,  the  reaction  underwent  variations,  very  much  in  the  same  way  as 
the  serum  reaction  is  changed,  in  syphilis,  by  salvarsan. 

During  the  course  of  intravenous  vaccine  injections,  the  positive  reaction,  in 
favourable  cases,  becomes  less  positive  ;  sometimes  it  returns  for  a  time  to  a  strong 
positive,  and  again  becomes  yet  more  diminished  in  intensity,  until  finally  it 
becomes  negative.  The  average  number  of  injections  required  to  obtain  a  negative 
reaction,  is  about  10.  Sometimes  even  that  number  is  insufficient.  If  too  big  doses 
are  given,  the  complement  fixation  test  becomes  negative,  but  the  symptoms  are 
aggravated,  and,  when  the  latter  have  quietened  down,  the  reaction  becomes 
positive  again. 

Three  patients  suffering  from  syphilis,  but  not  infected  with  gonorrhoea,  were 
injected  intravenously  with  the  vaccine.  Their  serum  gave  a  negative  result  with 
the  gonococcal  fixation  test,  and  remained  negative  after  the  injection.  The 
Wassermanu  reaction  was  also  uninfluenced. 

If  the  reaction  is  negative,  before  treatment  is  commenced,  it  becomes  positive 
immediately  after,  and  if  a  negative  reaction  is  gradually  obtained  by  the  use  of 
several  injections,  a  provocative  injection  some  time  later  will  not  give  rise  to  a 
positive  reaction.  If,  on  the  other  hand,  the  treatment  is  inadequate,  and  the 
reaction  becomes  negative  as  the  result  of  a  latent  stage  being  produced,  a 
provocative  injection  will  in  such  cases  give  rise  to  a  positive  reaction. 

3.  Sensitised  Vaccines. — Besredka^^"^^  originated  this  method,  based,  as  it 
was,  on  the  discovery  by  Ehrlich  and  Morgem-oth,  that  every  cell,  when  brought  into 
contact  with  its  specific  antibody,  fixes  it,  to  the  exclusion  of  every  other  substance 
which  may  be  present.  Applying  this  principle,  Besredka  uses  the  vaccine  to 
abstract  specific  antibody  from  an  immune  serum  ;  he  then  gets  rid  of  the  serum, 
and  uses  the  combination  of  vaccine  and  antibody  as  sensitised  vaccine. 

It  has  been  experimentally  proved  that  sensitisation  of  a  vaccine  enormously 
reduces  its  toxicity.     Thus  Besredka  found  that  "2  to  "1  c.c.  of  a  48  hours'  agar 


TREATMENT   OF   GONOERHOEAL   INFECTIONS    BY    VACCINES.  445 

culture  of  plague  destroyed  by  heat,  killed  a  mouse  in  48  hours,  but  that,  after 
sensitisation,  20  to  30  tunes  the  dose  could  be  injected  without  producing  any 
symptoms  at  all.  Similar  observations  have  been  made  in  the  case  of  the  dysentery 
bacillus  and  other  micro-organisms.  Further,  the  immunity  conferred  on  animals 
injected  with  sensitised  vaccines  comes  on  very  rapidly  :  in  the  case  of  typhoid, 
it  has  been  found  after  only  24  hours.  The  details  of  these  experiments,  and  the 
whole  history  of  the  method,  with  references  to  the  literature,  are  to  be  found  in 
a  "  Critical  Eeview  of  the  Sensitised  Vaccine  of  Besredka,"  by  M.  H.  Gordon.^ 

Preparation  of  the  sensitised  vaccine. — -This  was  carried  out  according  to  the 
method  recommended  by  Besredka.^  ^°  ^^  The  bacterial  emulsion  of  a  fresh  living 
culture  is  counted.  It  should  be  a  strong  emulsion  (at  least  1000  million  per  c.c). 
To  a  measured  amount  of  this  (2  c.c,  for  example),  about  1  c.c.  of  the  hnmune 
serum  is  added  (Besredka  prefers  to  use  as  little  antibody  as  is  compatible  with 
sensitisation)  ;  the  mixture  is  left  at  room  temperature  for  12  hours,  as  at  the  end 
of  that  time  the  bacteria  are  deposited  at  the  bottom  of  the  tube  ;  the  serum  is 
now  pipetted  off,  and  is  replaced  with  saline,  then  the  tube  is  shaken  and  centrifuged. 
The  saline  is  then  pipetted  off,  and  replaced  by  more,  and  the  tube  again  centrifuged ; 
the  deposit  of  bacteria,  washed  free  of  serum,  is  finally  made  up  to  the  original  bulk 
with  .5  per  cent,  phenol  saline,  and  this  constitutes  the  sensitised  vaccine. 

The  Immune  Serum  used  in  Sensitising. 

1.  Immune  Horse  Serum. — Burroughs  and  Wellcome's  antigonococcus  serum 
is  the  serum  of  a  horse  immunised  by  subcutaneous  inoculation  with  several  strains 
of  the  gonococcus.  This  serum  gave  complete  fixation  of  complement;  it  was  used, 
as  already  mentioned,  as  one  of  the  +  +  +  controls  ;  as  it  contained  much  anti- 
body, it  was  reasonable  to  suppose  that  it  was  well  adapted  to  the  preparation 
of  a  sensitised  vaccine.  This  expectation,  however,  was  not  realised.  The  first 
experiments  made  with  this  sensitised  vaccine  were  unsatisfactory.     Local  effects 

.  were  not  bad  ;  unprovement  was  noted  in  the  joints  or  other  foci  of  infection,  and 
no  negative  phase  occurred,  but  bad  general  effects  were  produced — the  patients 
had  diffuse  pains,  felt  ill,  and  rises  of  temperature  occurred. 

2.  Human  Immune  Serum. — In  consequence  of  these  bad  effects,  it  was 
decided  to  continue  to  work  with  sensitised  vaccine,  but  in  preparing  it  to  use  for 
immune  serum,  human  serum  taken  from  the  vein  of  a  gonorrhoeal  patient. 
Such  a  serum  was  obtained  from  Case  74,  taken  at  a  time  when  it  gave  a 
strong  positive  result  in  the  complement  fixation  test,  subsequent  to  six  intravenous 
injections  of  the  autolysed  vaccine,  with  doses  at  weekly  intervals  of  5  to  20 
million. 


446  THE   BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT    OF   GONORRHOEA. 

The  sensitised  vaccine  made  with  this  serum  behaved  very  difierently  from 
that  prepared  with  the  immune  horse  serum.  Not  oul}-  did  the  symptoms  of 
the  disease  disappear  more  quickly,  but  the  reactions  were  practically  nil,  and 
no  toxic  phenomena  occurred,  and,  as  with  the  last  described  vaccine,  no  negative 
phase  was  produced.  Equally  beneficial  results  were  obtained  with  a  second 
sensitised  vaccine  (human),  made  with  the  serous  effusion  from  the  knee-joint 
of  Case  75.  A  third  preparation  was  made,  with  a  human  immune  serum  obtained 
from  Case  72,  but  the  results  obtained  were  unsatisfactory,  for  the  following  reasons. 
The  serum  which  was  used  for  sensitisation  was  over  five  weeks  old,  and  was 
+  +  +  both  before  and  after  the  process  ;  moreover,  it  was  amphoteric,  a  property 
which  was  destroyed  by  reinactivating  for  an  hour. 

From  recent  experience  I  have  learnt  that  gonococcal  joint  fluid  is  the  best 
with  which  to  sensitise  a  vaccine,  and,  failing  that,  a  serum,  provided  it  gives  a 
strongly  positive  complement  fixation  test  with  a  gonococcal  antigen. 

The  superiority  of  gonococcal  vaccine  sensitised  with  human  immune  serum,  over 
that  sensitised  with  immune  horse  serum. — The  causes  of  this  marked  difference 
seem  to  be  as  follows  : — 

The  gonococcus  emulsion  contains  probably  two  constituents — 
{a)  The  killed  bacteria  themselves. 
(b)  Endotoxines  liberated  from  them. 

To  produce  a  completely  sensitised  vaccine,  which  wiU  not  exert  an}'  deleterious 
effects,  it  is  necessary  to  employ  an  immune  serum  which  will  combine  with  or 
neutralise  both  {a)  and  (6) ;  in  other  words,  the  immune  serum  should  contain 
both  a  bactericidal  substance  and  an  "anti-eudotoxine."  Now,  it  is  known  from 
the  experiments  that  the  immune  horse  serum  did  undoubtedly  contain  some 
specific  antibody,  which  gave  a  strong  complement  fixation  test,  and  it  probably 
possessed  bacteriolytic  properties  which  brought  about  an  improvement  in  the 
diseased  foci ;  the  toxic  symptoms  not  being  benefited,  but  often  increased,  leads 
one  to  assume  that  it  contained  no  anti-endotoxines  ;  these  soluble  products, 
remaining  uncombined,  caused  the  ill  effects  which  occurred. 

The  human  immune  serum,  on  the  other  hand,  contains  all  the  antagonistic 
substances  elaborated  in  the  course  of  the  natural  disease.  These  will  include 
both  bactericidal  and  anti-endotoxic  substances,  since  the  micro-organisms  are 
living  and  multiplying  in  the  body,  while,  at  the  same  time,  some  of  them  are 
continually  being  destroyed  and  setting  free  their  endotoxines. 

The  sensitised  vaccines  were  first  employed  in  doses  of  20,  50,  and  100  millions 
on  three  successive  days.    But,  from  recent  experience,  I  have  found  it  better  to 


TREATMENT   OF   GONORRHOEAL   INFECTIONS   BY   VACCINES.  447 

start  with  100^  and  to  increase  the  dose  daily  up  to  5000"  in  the  following  doses  : — 
100«,  500«,  1000«,  2500«,  5000«,  and  to  give  the  highest  dose  once  a  month 
afterwards  for  three  mouths.  If  the  patient  exhibits  toxic  symptoms  before  the 
maxunum  dose  is  reached,  three  weeks  should  be  allowed  to  elapse  before  the 
dose  that  caused  the  toxic  symptoms  is  repeated,  and  then  the  subsequent  injections 
should  be  given  monthly,  and  continued  as  before.  In  some  cases,  very  much 
bigger  doses  than  those  mentioned  can  be  given  with  impunity,  and  with  very  good 
results  intravenously,  but  unfortunately  the  preparation  of  sensitised  vaccines  in 
big  doses  entails  much  labour. 

Changes  produced  in  the  Immune  Serum  by  the  Sensitising  Process. 

Since  the  sensitisation  process  consists  in  the  combination  of  the  antigen 
with  the  antibody,  it  should  be  possible  to  show  that  the  immune  serum  has  lost 
part,  or  the  whole,  of  its  antibody  content  thereby,  by  testing  the  serum  before  and 
after  the  process. 

The  following  tests  were  made  : — 

1.  Immune  Horse  Serum. — Sensitisation  of  an  emulsion  of  a  certain  strain 
"  A,"  1  c.c.  of  serum  to  1  c.c.  of  a  1000  million  per  c.c.  emulsion — 

Serum  before  sensitisation  process  +  +  +  (against  several  strains,  including  "  A  "). 
,,       after  ,,  ,,         +  +  +   (against  "  A "). 

I.e.,  no  apparent  loss  of  antibody,  with  1  c.c.  of  serum  to  1000  million  cocci. 

2.  Immune  Human  Serum  (Case  72). — Sensitisation  with  an  emulsion  of  a 
certain  strain  "  X,"  1  c.c.  of  serum  to  1  c.c.  of  a  5000  million  per  c.c.  emulsion — 

Serum  before  sensitisation  +  +  +  (against  several  strains,  including  "  X  "). 
after  „  +  +  +  (against  "  X  "). 

3.  The  same  Serum,  No.  72  :  Knee-joint  Fluid,  No.  75 — compared. — Both  used 
for  sensitising  emulsions  of  two  strains  "  C  "  and  "  L  "  in  the  proportion  of  1  c.c. 
of  fluid  to  8000  million  gonococci — 

No.  72.  Before  sensitisation. .         ..         ..         ..  ..[-  +  + 

„      After  sensitisation  with  strain  "  C  "        . .  . .         +  + 

„      After  sensitisation  with  strain  "  L  "        . .  . .  + 

No.  75.  Before  sensitisation. .         . .     +  +  +  ("  C  ")  +  with  "  L." 

„      After  sensitisation  with  strain  "  C  "        . .  . .  — 

„      After  sensitisation  with  strain  "  L  "        . .  . .  — 

4.  The  same  Two  Fluids  (72)  and  (75)  were  sunilarly  placed  with  emulsions 
of  four  strains,  including  "  C  "  and  "  L  "  in  the  proportion  of  1  c.c.  of  the  serous 

2f 


448  THE   BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   GONORRHOEA. 

fluid  to  700  million  cocci — and  the  complement  fixation  test  showed  no  appreciable 

difference  in  the  antibody  before  and  after  the  sensitisatiou  process. 

Inferences  from  the  Above. 

Test  3  shows  that  the  antibody  may  be  more  readily  taken  up  b_y  a  given 
strain  of  gonococci  from  one  immune  serum  than  from  another,  although  both 
give  a  strong  fixation  of  complement  in  the  presence  of  that  strain. 

From  the  other  tests  it  appears,  that  it  is  only  when  the  quantity  of  gonococci 
is  sufficiently  large,  in  comparison  with  the  amount  of  immune  sermii,  that  the 
latter  is  robbed  of  its  antibody  to  a  sufficient  degree  for  the  loss  to  be  detected  by 
the  complement  fixation  test.  In  other  words,  the  gonococci  do  not  absorb 
antibody  to  an  unlimited  extent. 

Conversely,  a  given  volume  of  strongly  immune  serum  will  sensitise  a 
comparatively  enormous  quantity  of  gonococci. 

Cases  of    Gonorrhoeal  Infection  in  which  the  Complement  Fixation  Test 

WAS  Negative  or  Doubtful. 

Before  proceeding  to  the  detailed  account  of  the  series  of  cases,  which  were 
systematically  vaccinated  with  the  aid  of  frequent  serum  tests,  it  is  necessary  to 
mention  a  few  cases  in  which  very  little  information  could  be  gained  by  the  test. 
This  latter  group  is  made  up  of  scattered  cases,  not  treated  by  me.  Some  received 
vaccines  subcutaneously.  For  the  most  part  the  local  treatment  in  these  cases 
seemed  inadequate. 

Of  these  doubtful  cases,  with  regard  to  the  first  serum  test  made  :  four  gave 
a  complete  —  ;   two  gave  a  +  result ;   two  gave  a  +  result. 

As  a  means  of  diagnosis,  the  test  was  a  failure  in  six  out  of  the  eight  cases. 
Three  gave  a  +  result,  at  some  time  or  other,  whilst  under  observation.  Three 
gave  a  +  result,  at  some  time  or  other,  whilst  under  observation.  One  case,  tested 
on  only  one  occasion,  was  —  ;    one  case,  tested  on  only  one  occasion,  was  + . 

Two  of  these  cases  may  serve  as  t5'pes  : — 

A.  Phyllis  C,  set.  21. — Gonorrhoea  and  arthritis  of  left  knee  and  right  ^\"iist. 
Irregular  pyrexia.  Vaginal  discharge,  in  which  the  gonococcus  was  identified 
both  in  films  and  culture.  Autogenous  vaccines  were  used  in  doses  of  2,  5,  10, 
20  million  at  intervals  of  three  days. 

Serum  test. — May  21,  1912  (before  vaccine)        . .         . .         . .         . .  — 

„  May  23,  1912  (forty-eight  hours  after  first  vaccine)        . .  — 

„  June  13,  1912  (two  weeks  after  fourth  vaccine)  . .         . .  — 

July  10,  1912  + 


TREATMENT   OF   GONORRHOEAL   INFECTIONS   BY   VACCINES.  449 

The  vaccines  in  this  case  apparently  did  no  good,  though  autogenous.     Never- 
theless, this  same  strain  fixed  complement  in  the  presence  of  a  positive  control 
serum.     Such  improvement  as  eventually  resulted  seemed  to  be  due  rather  to  a 
slow,  naturally  established  immunity,  than  to  one  induced  by  vaccines. 

B.  Stanley  C,  aet.  22. — Gonorrhoeal  arthritis.     Urethral  discharge  14  weeks 
previously,  followed  10  weeks  later  by  pain  and  swelling  of  one  testicle.     Treatment 
with  sensitised  vaccine  (made  with  the  immune  horse  serum). 

Serum  reaction  before  vaccine        . .         . .         . .         . .         . .         . .     ± 

„         ,,  forty-eight  hours  after      . .  . .  . .  . .  . .     — 

,,         ,,  five  days  after        . .         . .         . .         . .         . .         . .     — 

This  patient  responded  unfavourably  to  the  sensitised  vaccine.  Unfortunately 
I  did  not  have  the  opportunity  of  trying  the  human  serum  sensitised  vaccine. 

These  failures  to  give  a  marked  fixation  of  complement  do  not  seem  to  be 
sufficiently  explained  on  the  theory  that,  in  certain  cases,  the  infection  is  by  an 
atypical  gonococcus  {vide  supra  Teague  and  Torrey,  and  Watabiki).  These  doubtful 
or  negative  sera  were  tested  with  more  than  one  strain  of  gonococcus.  Case  A 
gave  a  negative  result,  even  against  her  own  strain. 

It  seems  more  likely  that,  for  some  reason  or  other,  such  cases  fail  to  elaborate, 
or  that  they  produce,  very  slowly,  the  specific  antibodies  necessary  to  recovery. 
Hence  the  small  benefit  of  vaccine,  as  in  Case  A. 

One  other  case,  not  included  in  the  series  about  to  be  described,  may  be  briefly 
alluded  to,  namely,  A.K.  The  serum  of  this  patient  was  persistently  -|-  -F  -I-,  at 
intervals  extending  over  a  month.  It  has  been  referred  to  in  the  first  part  of  the 
paper  as  having  been  used  as  a  positive  control.  No  change  in  this  reaction 
occurred,  even  after  vaccines.  Now,  no  adequate  local  treatment  was  employed  here. 
Hence  the  failure,  either  to  alter  the  complement  fixation  test,  or  to  cure  the 
patient.  There  must  be  a  continued  production  of  antibodies  in  response  to  the 
continued  presence  of  gonococci.  The  presence  of  the  former  alone  may  be 
insufficient.     Hence  the  value  of  supplementary  treatment. 

Complement  Fixation  Tests  with  the  Exudates. 
The  fluid  from  the  affected  joints  was  tested  in  three  cases  : — 

1.  Case  75      . .         . .         . .         . .         . .     Result  -I-  -|-  +  ;  do.  with  serum. 

2.  „     76 „        +  +  +; 

3.  Louisa  C,  gonorrhoeal  arthritis  of  knee         ,,  +      ;  ,.        >, 

The  effusions  1,  2,  were  tested  for  antigen,  against  a  known  positive  serum. 

Even  when  used  undiluted,  the  result  was  negative.     The  fluids  were  sterile  in 

culture.  ) 

2f2 


450 


THE    BIOLOGY,    CLINICAL   ASPECT  AND    TREATMENT   OF   GONOKRHOEA. 


Injection  of  the  exudates  for  therapeutic  purposes.— In  Cases  74  and  75  the  joint 
fluid  was  injected  subeutaneously.     No  improvement  took  place. 

Case  58. — Male,  ^t.  35.  Severe  case.  Subacute  posterior  urethritis,  chronic 
prostatitis,  and  arthritis  of  both  knees  and  ankles,  with  rheumatic  pains  about  the 
right  shoulder.     Subcutaneous  vaccines  (freshly  prepared,  not  autogenous). 


Serum  Test. 

Injection  of  Vaccine  subeutaneously. 

Therapeutic  Effect. 

Before 

Forty- eight 

Vaccine. 

Hours  after. 

First  injection — 5  million        

+  +  + 

Marked  local  and  general 
reaction. 

Second — 10  million  (eighth  day  after 

+  +  + 

+ 

Less  local   and   general  re- 

first). 

action. 

Third — 15  million  (eighth  day  after 

+  +  + 

+  +  + 

Only  slight  reaction  ;   joints 

second). 

improved. 

Fourth — 25  million  (two  weeks  after 

+ 

+  +  + 

No   reaction ;     patient  pre- 

third). 

viously  crippled,  able  to 
walk  with  ease. 

Fifth — 50  million  (eighth  day  after 

+ 

+  +  + 

General  health  and  nutrition 

fourth). 

improved. 

Case  59. — Male.  Case  illustrates  diagnostic  value  of  gonococcal  fixation  test. 
Gonorrhoea  12  years  ago.  Syphilis  two  and  a  half  years  ago,  treated  with  72 
mercurial  injections.  No  signs  or  symptoms  for  about  two  years.  Six  weeks  ago 
iritis  of  left  eye  occurred.  Wassermann  reaction  negative.  Gonococcal  fixation 
test  positive.  Iritis  cured  with  gonococcal  vaccines,  without  any  anti-sj'philitic 
remedies. 


Subcutaneous  Vaccine. 


Serum  Test  before 
Vaccine. 


Serum  Test  Forty- 
eight  Hours  after. 


First  injection 

Second — eighth  day  after  first 
Third  „        „  second 

Fourtli  ,,         ,,  third 

Fifth  „        .,  fourth 

Sixth  .,        „  fifth 


+ 

+  +  + 

+  + 

+ 


I 


TREATMENT   OF   GONORRHOEAL   INFECTIONS    BY    VACCINES. 


451 


Case  60. — Male.  Chronic  posterior  urethritis  and  prostatitis,  urethral  strictures. 
Thickening  of  left  epididymis  (due  to  gonorrhoea!  epididpiiitis  five  years  previously). 
Subcutaneous  vaccines — results  as  follows  : — 


Injection  of  Vaccine  subcutaneously. 


Serum  Test. 


Before 
Vaccine. 


Forty-eight 
Hours  after. 


Therapeutic  Effect. 


First  injection — 10  million     

- 

+  +  + 

Second — 50  million  (fourth  day  after 

+  +  + 

+ 

first). 

Third — 50   million   (third   day   after 

+ 

— 

second). 

One  week  later — serum  test 
Two  weeks  later  „ 

Six  weeks  later  „ 


Severe  local  reaction.  Ure- 
thral discharge  increased  ; 
pain  in  left  testicle  for 
twenty-four  hours. 

Reaction  as  before,  but  less 
in  degree. 

Local  reaction  worse  than 
before ;  general  reaction 
marked  ;  no  increase  of  dis- 
charge or  pain  in  testicle. 

—  Urethritis  still  persisted. 

-f         Finally    cured     only     after 

—  gradual       dilatation       of 
strictures. 


Case  61. — Male,  set.  31.  Chronic  posterior  urethritis  and  prostatitis.  Ordinary 
vaccine,  subcutaneously  (not  autogenous).  Eight  weekly  injections,  from  5  to 
200  million  gonococci.  Symptoms  completely  cleared  up.  No  improvement 
before  vaccine  treatment.  Purulent  urethral  discharge  foUowed  injections  of 
vaccine,  each  succeeding  discharge  being  progressively  less  in  intensity  and  duration. 
The  last  injection  of  vaccine  gave  rise  to  no  discharge. 

Case  62. — Female,  aet.  29.  Chronic  gonorrhoea.  Menstrual  disorders.  Vaccine 
treatment  with^ — ■ 

(a)  "  Gonargin  "  (a  commercial  polyvalent  vaccine),  50  million. 
(6)  Two  weeks  later,  20,  50,  and  100  million  sensitised  vaccine  (hnraune 
horse  serum)  on  three  successive  days. 


Time. 

Serum  Test. 

Therapeutic  Result. 

Before  gonargin     

Before  sensitised  vaccine 

Forty-eight  hours  after     

Six  days  after         

Three  weeks  after 

Six                „          

+  + 

-f  + 
+  + 

Local  reaction  slight ;  general  reaction  very 
bad  ;  discharge  temporarily  increased,  later 
less  than  before. 

Local  reaction  slight ;  general  reaction  severe  ; 
discharge  increased. 

Still  vaginal  discharge  ;   muscular  pains. 

General  health  improved  ;   stiU  discharge. 

452 


THE   BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   GONORRHOEA. 


Case  63. — Male,  ast.  32.     Chronic  posterior  urethritis.     Old  epididjiiiitis  (right). 
Vaccine  treatment  with — 

(a)  "  Gonargin  "  50  million. 

(b)  Five  days  later,  20,  50,  100  million  sensitised  vaccine  (horse  serum) 

on  three  successive  days. 


Time. 


Serum  Test. 


Condition  of  Patient. 


Before  gonargin 
After 


Before  sensitised  vaccine  ... 

Forty-eight  hours  after  sensitised 
vaccine. 


Fifth  day  after  sensitised  vaccine 

Tenth 

Twenty-first  day  after  sensitised 

vaccine. 
One  month  after  sensitised  vaccine 


+  + 


+  + 


Local  reaction  marked  ;  bad  general  reaction  ; 
discharge  increased  ;  right  epidid\'niis  pain- 
ful. 

First    sensitised    vaccine ; 
general  reactions. 

Second   sensitised   vaccine  ; 
general  reactions. 

Third    sensitised    vaccine  ; 
general  reactions. 

Discharge  considerably  less. 
,,  less. 

„  ceased. 

Xo  threads  in  urine. 


slight  local  and 
slight  local  and 
slight    local    and 


Case  6i. — Male.  Chronic  posterior  utethritis  and  prostatitis.  "  Gonargin  "  three 
injections  of  50  million.  Human  sensitised  vaccine,  three  weeks  later,  20,  50  and 
100  million  on  successive  days. 


Time. 

Serum  Test. 

Therapeutic  Effect. 

Day  of  first  injection  of  gonargin... 
Forty- eight  hours  after  first  gonar- 
gin. 

+  + 

Local  reaction,  no  general ;    discharge  much 
increased. 

Forty-eight    hours    after    second 

_ 

Less  local  reaction  ;    less  marked  increase  of 

gonargin. 
Fort3'-eight     hours     after     third 

gonargin. 
Day  before  sensitised  vaccine 

+ 

discharge. 
Sbght    local    reaction ;      local    condition    no 

better. 
Local  condition  as  bad  as  at  the  beginning  of 

treatment. 

Forty-eight  hours  after  trio 

+  +  + 

Xo   general,   very   slight   local   reaction   after 
first,  second  and  third  sensitised  vaccine. 

One  week  later       

Three  weeks  later 

+  + 

_ 

After  first,  discharge  not  increased. 

,,      second,  chscharge  diminished. 

„      third,  discharge  ceased  entirely. 
Complete  recovery. 

TREATMENT   OF   GONORRHOEAL   INFECTIONS   BY    VACCINES. 


453 


Case    65. — Gonorrhoea  of  four  months'   duration.       Unilateral  epididymitis. 
Gonargiu."     Sensitised  vaccine  (horse),  20,  50, 100  million. 


Day. 

Serum  Test. 

Therapeutic  Effect. 

First  injection,  gonargin  ... 

... 

Slight  local  and  general  reaction ;  severe 
"  focal  "  reaction,  namely,  acute  discharge, 
and  pain  and  swelling  of  affected  testicle. 

Second  injection,  gonargin 

More  marked  local,  no  general  reaction ; 
acute  discharge  ;   no  swelling  of  testicle. 

Day    of    sensitised    vaccine, 

20 

— 

No  reaction  ;   discharge  diminished. 

million. 

Day   of    sensitised    vaccine. 

.50 

+  _ 

Slight  local  and  general  reaction. 

million. 

Day   of   sensitised   vaccine, 

100 

— 

Slight  local,  more  general,  reaction. 

million. 

Three  davs  later     

+  +  + 

Eight         „              

+  +  + 

Pains  ;   malaise  ;   discharge  increased. 

Ten             „             

... 

+  +  + 

C4eneral  condition  much  the  same. 

Seventeen  days  later 

+ 

No  malaise  ;   discharge  ceased. 

Twenty-one  daj-s  later 

+ 

Twenty-eight  days  later   . . . 

+  - 

Still  slight  discharge  in  the  morning. 

Case  G6. — Chronic  gonorrhoea.  Fourth  recurrence.  Strictures.  Gonargin,  50 
million.  Fourteen  days  later,  20,  50,  and  100  million  sensitised  vaccine  (horse) 
on  successive  days. 


Time. 


Serum  Test. 


Therapeutic  Effect. 


Bejore  treatment   ... 
Gonargin  injected 

Sixth  day  after  gonargin 

Day    of    sensitised    vaccine,    20 

million. 
Tliird  day  after  trio 
First  week         ,, 
Second  week     „ 
Third     „ 
Fourth  „ 
Sixth      ,,  „ 


Slight  local,  no  general  reaction  ;    discharge 

increased. 
Fever  and  general  malaise  ;  discharge  copious. 
No  reaction  ;   discharge  decreased. 


Slight  discharge  persisting,  due  to  obstinate 
strictures. 


454 


THE   BIOLOGY,    CLINICAL   ASPECT   AND    TREATMENT   OF   GONORRHOEA. 


Case  67. — Female,  set.  26.     Latent  case.     Later  arthritis  of   right  knee-joint. 
Vague  pains  in  limbs  and  pelvis. 


Time. 

Serum  Test. 

Therapeutic  Effect. 

Before  treatment 

+  + 

First  injection  of  gonargin 

One  week  after       

Second  injection  of  gonargin 

One  week  after       

Third  injection  of  gonargin 
One  week  after 

+  + 

Slight  local,  severe  general  reaction. 
Condition  generally  improved. 
Severe  local  and  general  reaction. 
Vaginal  discharge. 
Severe  general  reaction. 

Two  weeks  after     ... 
Sensitised  vaccine,  20  million 
f,          ,,            50       ,, 
100      „ 

■Portj^-eiglit  hours  later     

Two  weeks  later     

+ 

No  marked  improvement. 
Reactions  both  local  and  general. 

+  +  + 
+  + 

Fluid  in  knee-joint  disappeared. 

Four         „             

Six            „•            

+ 

No    pains    or    toxic    symptoms ;     patient's 
general  condition  enormously  improved. 

Case  68. — Male.    Pains  in  knee  and  finger-joints.     Latent  gonorrhoea.    Treated 
with  human  sensitised  vaccine.     Eapidly  improved. 


Time. 


Condition  of  Patient. 


Before  treatment    ... 
Sensitised  vaccine,  20  million 
,,         ,,  yO      ,, 

100      „ 
Three  days  later     ... 
Fourteen  days  later 


Pains  in  joints  ;   threads  in  urine. 
No  reaction  ;   threads  fewer  in  urine. 
Joint  pains  disappeared  ;    a  few  threads 
xu'ine. 

Urine  clear ;  no  symptoms. 


Cases  69  and  70. — Male,  a3t.  56  ;  woman,  set.  29.  Chronic  arthritis  (of  osteo- 
arthritic  type).     Similar  cases. 

Case  69  had  chronic  urethritis  and  old  syphilis.  The  Wassermann  reaction  and 
gonococcal  fixation  test  both  positive.  Partial  improvement  of  joint  after  salvarsan 
ind  a  course  of  mercury  and  iodides.     Wassermann  reaction  remained  positive. 

Further  improvement  six  weeks  later,  after  the  three  injections  of  sensitised 
(horse)  vaccine.    As  in  other  cases,  toxic  symptoms  followed  the  injections  of  vaccine. 

Case  70. — No  signs  of  gonorrhoea.     Fixation  test  with  gonococcus,  positive. 

Human  sensitised  vaccine,  25,  50  and  100  million. 

No  toxic  symptoms  at  all.     Some  improvement  in  joint. 

In  both  the  arthritis  (hip)  was  of  too  long  standing  to  be  cured.  In  both  cases 
the  gonococcal  fixation  test  became  negative  about  three  weeks  after  the  last  vaccine. 


TREATMENT   OF   GONORRHOEAL   INFECTIONS   BY   VACCINES. 


455 


Case  71. — Female.     Gonorrlioeal  arthritis  (knee-joint).      Treated  with  human 
sensitised  vaccine  with  marked  success. 


Time. 

Serum  Test. 

Condition  of  Patient. 

Before  treatment 

+  + 

Right   knee   swollen    and    painful,    and    con- 
taining fluid. 

Sensitised  vaccine,  20  million 

1 

50      „ 

\ 

No   general   reaction ;     no    focal   reaction   in 

100      ,. 

joint ;   slight  local  reaction. 

Forty-eight  hours  later     

+  +  + 

One  week  later       

+  +  + 

No  pain  in  joint ;   fluid  gone. 

Two  weeks  later 

+  + 

Four  weeks  later    ... 

Improvement  maintained. 

Case  72. — Male.  Gonorrhoeal  arthritis.  Severe  case.  Both  knees,  both  ankles, 
both  elbows  and  both  shoulder-joints,  also  wrists  and  fingers  were  involved. 
Previous  unsuccessful  treatment  with  three  injections  of  vaccine  (commercial 
stock),  and  four  injections  of  another  stock,  going  up  to  doses  of  2000  million. 
Treatment  with  sensitised  vaccines  (horse). 


20  million  ... 

50     „ 
100      „ 

Three  days  later 
Seven         „ 
Thirteen     „ 


Marked  focal  reaction  in  all  affected  joints. 
Bad  local,  slighter  focal,  reaction. 
Severe  local,  no  focal,  reaction. 

Swelling  of  -nTists  and  hands  gone  ;  other  joints  better. 
Improvement  in  all  joints  very  marked. 

General  arthritis  improved   enormously ;    patient  able   to  walk, 
and  gaining  in  health  and  nutrition. 


Serum  reaction  was  positive  {  +  +  +)  throughout. 


Case  73. — Male,  set.  18.  Subacute  urethritis.  Arthritis  of  left  wrist-joint 
and  tenosynovitis.  No  involvement  of  posterior  urethra.  Intravenous  vaccine, 
autolysed,  3  million. 


Time. 

Serum  Test. 

Result. 

Before  vaccine 
Twenty-four  hours  after   ... 

Forty-eight  hours  after     

Ten  days  after        

^ 

+  + 

—              No  reaction  of  any  kind. 
+  -f           Arthritis  entirely  gone. 
+  -f           Discharge  persisted. 

456 


THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   GONORRHOEA. 


Case  74. — Chronic  prostato-urethritis.  Gonorrhoeal  arthritis  of  both  knees  and 
ankles.  Previously  has  had  iritis  four  times.  Intravenous  vaccines  (weekly). 
Much  improved.  • 


Time. 


Serum  Test. 


Result. 


Before  first  vaccine  (5  million)     ... 

+  + 

Forty-eight  hours  later     

+  + 

Temporary  pyrexia  ;  joints  felt  better. 

Five  days  later       

+ 

Joints  still  felt  better. 

Before  second  vaccine  (5  million) 

+ 

Fortj'-eight  hours  later     

+  - 

No  pyrexia  or  discomfort ;  joints  better. 

Before  third  vaccine  (10  million)... 

+ 

General  condition  improved. 

Forty-eight  hours  later 

+  - 

Slight  toxic  pains  ;  joints  better. 

Before  fourth  vaccine  (10  million) 

+  + 

Forty-eight  hours  later     

-f + 

No  pyrexia  ;  pains  in  hip  and  back. 

Before  fifth  vaccine  (15  million)  ... 

+  -f-f 

Swelling  and  fluid  in  joints  gone ;    discharge 

less. 
Iritis  developed  in  right  eye. 

Forty-eight  hours  after     

+  +  + 

Before  sixth  vaccine  (20  million)... 

+  - 

Forty-eight  hours  later     

+  +  + 

Bad  toxic  pains  ;  no  pyrexia. 

Before  seventh  vaccine  (20  million) 

+  + 

Iritis  improved. 

Forty-eight  hours  later     

+ 

Iritis  gone ;    discharge  ceased  ;    joints  much 
better. 

Nine  days   after  eighth   vaccine 

+ 

Patient  walks  well. 

(20  million). 

Three  weeks  after  eighth  vaccine 

— 

Improvement  maintained. 

(20  million). 

Case  75. — Male,  set.  21.  Gonorrhoeal  arthritis.  Effusion  in  right  knee-joint, 
pain  and  swelling  of  left  ankle  and  right  hand.  Intravenous  vaccines — five  injections 
of  10  million  doses. 


Time. 


Serum  Test. 


Result. 


Before  vaccines 
First  injection 
Five  days  later 
Eight  days  later     ... 
Forty-eight    hours    after   second 

vaccine. 
Before  third  vaccine 
Forty-eight  hours  later 
Before  fourth  vaccine 
Forty-eight  hours  later 
Before  fifth  vaccine 
Forty-eight  hours  later 


+  +  + 

+  +  + 

-t- 

+  + 

+  +  + 

-f -f 
-f-f  + 
+  +  + 
-f +  -f 
+  +  + 


No  reaction  ;  joint  movements  freer. 
Fluid  aspirated  from  joint.* 

Marked  improvement ;   slight  pyrexia. 


Knee  filled  up  again. 

No    reaction;     knee-joint     unaltered;     other 

joints  much  improved. 
General  condition  much  improved  ;    all  other 

joints  recovered  except  knee. 


*   Vide  svpra,  p.  445, 
with  the  Exudates." 


'  Human  Immime  Serum,"  and  p.  449,  "  Complement  Fixation  Tests 


TREATMENT   OF   GONORRHOEAL   INFECTIONS   BY   VACCINES. 


457 


Case  76. — Male,  aet.  21.  Gonorihoeal  arthritis.  Effusion  in  left  knee-joint. 
Arthritis  of  both  temporo-mandibular  joints,  and  many  other  joints.  Intravenous 
vaccines,  five  injections  of  10  million  doses. 


Time. 

Serum  Test. 

Condition. 

Before  vaccines 

+  + 

Patient  quite  crippled  ;   very  emaciated. 

Forty-eight     hours     after     first 

+  + 

Temperature  rose  to  100°  -4  ;  no  discomfort. 

vaccine. 

Five  days  after  first  vaccine 

+ 

Before  second  vaccine       

+  -      ■> 

Forty-eight    hours    after   second 

+  + 

No    reaction ;      patient    feels    better        joint 

vaccine. 

> 

aspirated.  * 

Four  days  after  second  vaccine   ... 

+  +      J 

Forty-eight    hours    after    third 

No  reaction. 

vaccine. 

Four  days  after  third  vaccine 

— 

All  the  joints  are  better. 

Forty-eight    hours    after   fourth 

+  +  + 

Toxic  pains  ;  patient  can  walk  a  little. 

vaccine. 

Five  days  after  fourth  vaccine    ... 

+  +  + 

General  improvement  very  marked. 

Forty-eight     hours     after     fifth 

— 

Temperature  rose  to  100°  ;   toxic  pains. 

vaccine. 

Two  weeks  after  fifth  vaccine 

Enormous  improvement  in  joints  and  general 
health. 

*   Vkle  supra,  p.  44.5,  "  Human  Immune  Serum,"  p.  449,  "  Complement  Fixation  Tests  with 
the  Exudates." 


Summary  of  Results. 

(a)  The  serum  of  normal  persons,  and  of  patients  suffering  from  diseases  other 
than  gonorrhoea  (including  syphilis),  gives  no  fixation  of  complement  in  the  presence 
of  the  gonococcal  antigen. 

(b)  The  serum  of  the  majority  of  gonorrhoeal  cases  with  metastatic  lesions, 
such  as  arthritis,  gives  a  positive  reaction,  generally  of  marked  degi-ee. 

(c)  The  serum  of  a  minority  of  such  cases  gives  either  a  feeble  or  negative 
reaction.  As  a  rule,  however,  even  in  such  cases,  a  positive  or  feebly  positive 
reaction  occurs  at  some  time  or  other. 

The  injection  of  vaccines  may  markedly  alter  the  serum  reaction  in  the 
following  ways  : — 

{a)  Vaccine  injection  in  normal  or  non-gonorrhoeal  individuals  produces  no 
change  in  the  serum  reaction,  which  remains  negative. 

(6)  Vaccine  injection  may  convert  a  strong  positive  to  a  less  marked  or  even 
negative    reaction,    of    temporary    duration.      This    temporary    change   may    be 


458  THE   BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   GONORRHOEA. 

considered  as  a  "  negative  phase."  A  second  injection  is  followed  by  a  similar 
phenomenon  of  lesser  degree. 

Subsequently  the  reaction  may  remain  positive  for  some  time,  even  though 
improvement  {e.g.,  Case  75)  occurs.  On  the  other  hand,  the  positive  reaction  which 
returns  after  the  temporary  change,  may  progressively  diminish,  and  finally  the 
reaction  becomes  negative,  and  still  remains  negative  weeks  later  {e.g.,  Case  74). 
After  complete  cure,  the  reaction  eventually  becomes  negative,  and  remains  negative 
after  a  "  provocative  injection  "  of  vaccine. 

(c)  The  doubtful  or  negative  result  may  be  altered  after  vaccine  treatment. 
It  may  become  positive.  A  second  injection  may  produce  further  change  in  the 
reverse  direction.     Further  injections  may  render  it  entirely  negative. 

{d)  There  is,  therefore,  an  analogy  between  these  phenomena  and  the  changes 
in  the  serum  reaction  in  syphilis,  following  the  injection  of  salvarsan.* 


Conclusions. 

1.  The  complement  fixation  test  in  gonorrhoea!  infections  is  a  valuable  aid 
to  diagnosis,  and  can  be  used  for  regulating  vaccine  treatment. 

2.  If  the  disease  is  in  the  latent  stage,  and  the  body  has  need  to  form  antibodies, 
the  result  of  an  injection  of  potent  vaccine  will  be  to  stimulate  their  production. 

If  antibodies  are  already  present,  the  injection  of  vaccine,  in  sufficient  amount, 
will  temporarUy  neutralise  or  inhibit  the  same.  What  actually  happens  cannot 
be  absolutely  proved,  but  my  own  opinion  is,  that  the  lipoid-globulin  molecule 
is  broken  up.  The  period  of  inhibition  corresponds  with  that  of  the  negative 
phase,  therefore  there  may  be  some  connection  between  this  phase  and  the  hydrolysis 
of  the  lipoid-protein  molecule.  Let  us  look  at  this  problem  a  little  more  closely. 
There  is  no  doubt  that  the  lipoid-globuUn  molecule,  in  syphilis,  is  broken  up  by  the 
first  and,  occasionally,  by  the  second  dose  of  salvarsan.  This  is  more  likely  to  occur 
in  the  late  than  in  the  early  stages  of  the  disease.  The  previously  positive 
Wassermann  reaction  becomes  negative,  and  the  serum  globulin  is  diminished. 
If  the  serum  globulin  is  diminished,  it  might  be  expected  that  any  concurrent 
disease  from  which  the  patient  was  suffering  would,  during  this  period,  be 
aggravated.  Clinically,  such  is  the  case,  and  many  are  the  patients  who,  con- 
sidering themselves  cured  of  gonorrhoea,  have  noticed  a  short  return  within  24 
hours  after  the  salvarsan  injection.  Several  instances  relating  to  other  diseases 
could  be  given.  If  the  patient  develops  a  negative  phase  after  a  gonococcal  vaccine, 
note  how  the  symptoms  are  temporarily  aggravated,  and  how  often  an  attack  of 
Herpes  'preputialis  supervenes. 


TREATMENT   OF   GONORRHOEAL   INFECTIONS    BY    VACCINES.  459 

The  reason  why  salvarsan  should  exert  this  action  in  a  more  jnonounced 
degree  in  late  than  in  early  cases — and,  after  all,  the  negative  phase  is  more  common 
in  the  chrorue  than  in  the  acute  stages  of  the  infection — is  possibly  owing  to  the  fact 
that  the  older  the  specificity  in  the  lipoid-globuliu  molecule,  the  greater  the  number 
of  fatty  acid-groups  it  will  have  attached  to  it.  The  greater  the  number  of  fatty 
acid-groups,  the  less  potent  the  therapeutic  action  of  the  molecule  becomes,  and 
the  greater  the  ease  with  which  it  can  be  hydrolysed. 

The  lipoid-globulin  appears  to  be  manufactured  in  the  lymphocytes ;  hence 
one  would  expect,  since  improvement  follows  further  administration  of  salvarsan 
and  a  vaccine,  that  the  number  of  circulating  lymphocytes  is  increased.  Such 
is  found  to  be  the  case,  and  many  clinicians  will,  no  doubt,  have  observed  a  swelling 
of  the  lymphatic  glands  after  a  few  doses  of  salvarsan  and  a  vaccine  have  been 
given. 

This  results  in  new  lipoid-globulin  molecules  being  formed  ;  in  other  words, 
fresh  antibody  ;  hence  the  unprovemeut  in  the  condition  when  the  negative  phase 
has  passed. 

3.  The  injection  of  a  potent  vaccine  promotes  a  new  artificial  kind  of  immunity, 
more  effectual  than  that  already  established  in  the  infected  individual. 

Of  the  three  methods  of  vaccine  treatment  tried,  the  intravenous  autolysed 
solution  comes  midway  in  its  therapeutic  action  between  an  ordinary  vaccine  and 
a  sensitised  vaccine — both  the  latter  given  subcutaneously,  or  intramuscularly. 

The  vaccine  sensitised  with  a  human  antigonococcal  serum  is  far  superior  to 
the  vaccine  sensitised  with  immune  horse  serum,  and  its  action  is  most  marked  when 
given  intravenously. 

4.  Vaccine  treatment,  provided  it  is  only  supplementary  to  the  right  local 
and  general  treatment,  is  in  many  cases  necessary,  before  a  cure  can  be  obtained. 

As  it  is  not  always  possible  to  get  a  sensitised  vaccine,  one  must  be  satisfied 
with  an  ordinary  vaccine,  prepared  according  to  the  directions  above  given.  The 
doses  will  vary  according  to  the  potency  of  the  vaccine,  so  one  generally  has  to  feel 
one's  way,  if  the  vaccine  is  entirely  a  new  one.  I  usually  begin  with  5^,  and 
gradually  increase  the  dose  weekly,  until  the  last  dose  ceases  to  produce  any  focal 
reaction.  When  this  dose  has  been  ascertained,  I  then  give  it  once  a  month  for  the 
next  six  months.  This  procedure,  which  is  not  yet  in  general  use,  will  ver}^  often 
prevent  a  case  from  relapsing.  I  also  think  it  is  wise,  even  in  the  acute  cases,  while 
the  disease  is  hmited  to  the  urethra,  to  prescribe  vaccines,  as  they  are  certain  to 
raise  the  patient's  natural  immunity. 

Before  closing  this  chapter,  there  is  just  one  other  point  concerning  which  a 
little  speculation  is  justifiable.     I  refer  to  the  theory  of  sensitisation.     From  other 


460  THE    BIOLOGY,    CLINICAL   ASPECT   AND   TREATMENT   OF   GONORRHOEA. 

statements  made  in  this  book,  the  reader  will  remember  that  antigen  and  antibody 
contain  homologous  stereo-chemical  molecules,  and  that,  when  they  meet,  adsorption 
results.  There  is  a  limit  to  the  adsorptive  capacity  of  an  antigen  ;  therefore,  if 
the  antigen  has  been  charged,  so  to  speak,  with  antibody,  before  it  is  injected,  it 
will  be  seen  that  it  cannot  take  up  any  more  when  it  enters  the  host.  When  an 
ordinary  antigen  is  injected,  it  fixes  itself  on  to  the  already  existing  antibody, 
adsorption  results,  lipoid-globulin  molecules  are  precipitated,  and  then  hydrolysed. 
If  the  antigen  is  already  charged  beforehand,  it  cannot  adsorb  more  antibody  ; 
therefore,  there  is  no  negative  phase.  From  this  the  assumption  may  hastily  be 
made  that  the  end  result  is  the  same  in  both  cases,  or  that  the  therapeutic  result 
of  an  ordinary  vaccine  is  the  same  as  that  of  a  sensitised  vaccine.  The  apparent 
difference  in  the  clinical  results  might  be  explained  by  the  absence  of  the  negative 
phase,  when  a  sensitised  vaccine  is  used,  and  by  the  fact  that  very  much  larger 
doses  may  be  given.  I  think  there  is  still  another  factor  at  work,  and  that  is  the 
physical  alteration  which  takes  place  in  the  antigen,  when  it  has  adsorbed  its 
homologous  molecule  in  the  body.  As  I  have  made  no  adequate  study  of  this 
physical  alteration,  and  as  the  possible  results  might  have  a  considerable  influence 
upon  some  of  our  therapeutic  agents,  it  would  be  as  well  to  leave  the  subject  here, 
and  wait  till  more  experiments  have  been  undertaken. 

REFERENCES. 

1  Gordon,  1912,  "  Quart.  Journ.  Med.,"  v,  509. 

2  Klein,  1910,  "  Lancet,"  i,  1255. 

3  McDonagh,  1912,  "  Brit.  Med.  Journ.,"   i,  1287. 

^  Schwartz  and  M'Xeil,  1911,  "  Am.  Journ.  Med.  Sc,"  cxli,  693. 

"  league  and  Torrey,  1907,  "  Studies  from  Dept.  of  Path.,  Cornell  Univ.,  N.Y.,"  vii  ;  and 
"  Journ.  Med.  Research,"  Boston,  1907-8,  x\ii,  223. 

°  Watabiki,  1910,  "Journ.  Infect.  Diseases,"  vii,  159. 

'  Wright  (1909),  "  Studies  in  Immunisation,"  London. 

*  McDonagh  and  Klein  (1913),  "  Journ.  of  Path,  and  Bact.,"  xvii,  599 

9  Besredka  (1902),  "  Ann.  de  I'Instit.  Past.,"  xvi,  918. 
>»  Besredka  (1902),  "  Compt.  rend,  de  I'Acad.  des  Sci.,"  cxxxiv,  1330. 
"  Besredka  (1910),  "  Bull,  de  I'Instit.  Past.,"  viii,  241. 


CHAPTER  XL. 
PHIMOSIS  AND   PARAPHIMOSIS. 

Phimosis. 

The  word  phimosis  is  derived  from  the  Greek  (pifio^,  a  band.  Phimosis 
may  be  congenital  or  acquired.  Only  the  acquired  form  need  be  discussed,  because 
the  only  thing  to  say  about  the  congenital  form  is,  that  the  patient  should  be 
ciicumcised.  Acquired  phunosis  is  due  to  inflammation,  and  it  may  be  caused 
by  any  venereal  disease.  There  are,  clinically,  two  kinds  of  phimosis,  and  if  this 
point  be  borne  in  mind,  it  is  usually  possible  to  make  a  diagnosis  of  the  underlying 
condition  at  sight.  If  a  man  with  phunosis  consults  you,  first  notice  if  the  prepuce 
is  very  red  and  swollen  ;  if  so,  then  it  is  an  acute  inflammatory  phimosis,  and  is 
probably  caused  by  gonorrhoea,  a  soft  sore,  or  Balanitis  erosiva  et  gangraenosa. 
If  the  prepuce  is  red  and  swollen,  the  swelling  is  uniform,  painful  to  the  touch,  and 
there  is  always  a  purulent  discharge.  A  phimosis  caused  by  Balanitis  erosiva  et 
gangraenosa  is  the  most  painful,  then  that  caused  by  a  soft  sore,  while  a  gonococcal 
phimosis  is  not,  as  a  rule,  very  painful.  If  the  j^repuce  is  not  red,  and  is  swollen 
in  only  one  part,  or  is  only  red  in  that  part  which  is  swollen,  and  if  the  discharge 
is  thin,  you  may  be  quite  sure  that  the  patient  has  a  primary  sore  in  the  corona, 
and  that  that  part  of  the  foreskin  which  is  the  mo.st  swollen  marks  its  position. 
A  syphilitic  phimosis  is  generally  painless. 

In  the  acute  inflammatory  phunosis,  the  foreskin  should  be  slit  up  at  once, 
but  circumci.sion  should  not  be  done.  In  the,  so  to  speak,  non-inflammatory 
phimosis,  i.e.,  the  syphilitic  phimosis,  non-inflammatory,  since  the  phimosis  is 
really  due  to  a  diffuse  sj-philitic  lymphangitis  of  the  prepuce,  circumcision  can  be 
delayed  until  the  lymphangitis  has  subsided  somewhat  under  salvarsan.  Cir- 
cumcision should  be  done  later,  so  that  mercurial  ointment  may  be  rubbed  into 
the  chancre. 

Another  clinical  point  in  the  soft  sore  phimosis,  is  that,  in  several  cases,  there 
are  some  sores  on  the  tip  of  the  foreskin.  When  a  phimosis  is  very  red,  shiny,  and 
stony  hard,  the  diagnosis  of  a  malignant  epithelioma  should  be  considered. 


462  subsidiary  venereal  diseases. 

Paraphimosis. 

Paraphimosis  may  occur  mechanically,  by  a  patient's  retracting  his  foreskin 
and  being  unable  to  pull  it  forward  again,  but  it  is  more  often  due  to  some 
inflammatory  condition.  There  are  two  kinds  of  paraphimosis — ihe  Paraphimosis 
interna  and  the  Paraphimosis  externa,  the  former  being  the  rarer  of  the  two. 

Paraphimosis  externa  can  only  occur  if  the  limbus  of  the  prepuce  is  particularly 
narrow.  The  limbus  is  formed  by  circular  fibres  of  connective  tissue  in  the  fore 
part  of  the  prepuce.  If  the  limbus  is  narrow,  it  will  naturally  follow  that  retraction 
of  the  foreskin  may  be  possible,  but  that  the  corona  will  make  reposition  difficult. 
This,  then,  leads  to  considerable  swelling  of  the  external  lamella  of  the  prepuce. 

Owing  to  the  narrowness  of  the  limbus,  and  to  the  fact  that  the  inner  lamella 
of  the  prepuce  is  turned  in,  it  wUl  follow  that  all  the  pus  that  was  in  the  corona 
will  now  be  in  between  the  two  lamellae  of  the  foreskin.  Therefore,  unless  the 
condition  be  relieved  quickly,  the  increased  inflammation  will  further  aggravate 
the  condition,  so  that  sloughing  of  the  foreskin  may  easily  occur. 

Provided  gangrene  has  not  set  in,  attempts  at  reposition  should  be  made. 
As  the  corona  is  the  hindrance  to  natural  reposition,  the  first  thing  to  do  is  to  reduce 
the  size  of  the  glans  penis.  Cold  applications  or  tying  round  with  indiaiubber 
will  usually  effect  reduction  ;  then  reposition  becomes  simple.  As  Paraphimosis 
interna  is  not  so  noticeable  as  Paraphimosis  externa,  most  of  the  cases  seek  advice 
when  it  is  too  late.  Under  these  circumstances,  the  best  procedure  is  to  cut  the 
limbus,  wash  out  all  the  discharge  with  hydrogen  peroxide,  and  then  keep  the 
area  as  dry  as  possible,  by  using  iodoform,  isoform,  or  dermatol  powder.  Owing 
to  the  pent  up  pus  between  the  two  lamellae  of  the  prepuce,  a  dorsal  lymphangitis 
of  the  penis,  and  bilateral  inguinal  adenitis,  with  abscess  formation  in  either 
condition,  is  a  complication  which  often  has  to  be  feared. 

In  the  Paraphimosis  externa,  the  limbus  is  usually  wide  enough,  the  condition 
being  produced  primarily  by  an  oedema  of  the  inner  lamella  of  the  prepuce.  If 
a  case  of  Paraphimosis  externa  be  examined,  it  will  be  noted  that  a  band  usually 
exists  only  on  the  dorsum,  and,  according  to  its  severity,  on  the  lateral  walls  of  the 
penis,  posterior  to  the  prepuce.  The  base  is,  as  a  rule,  not  constricted,  but  it  is 
very  oedematous.  Unless  the  condition  be  quickly  relieved,  a  fissure  is  very 
likely  to  occur  in  the  dorsal  constriction,  and  this  is  often  the  beginning  of  gangrene. 

In  trying  to  replace  the  prepuce,  the  oedematous  foreskin  should  be  held  with 
the  fingers  of  both  hands  and  pushed  forwards  over  the  glans,  which  should  at  the 
same  time  be  pressed  backwards  with  both  thumbs.  If  there  is  a  fissure  already, 
or  if  there  is  a  good  chance  of  producing  one,  by  prolonged  inability  at  reposition, 
it  is  best  to  resort  to  another  method. 


PHIMOSIS   AND   PARAPfflMOSIS.  463 

The  chief  cause  which  prevents  reposition  is  the  oedema  of  the  dorsal  part  of 
the  foreskin  ;  therefore,  if  this  can  be  reduced,  replacing  the  foreskin  is  an  easy 
matter.  Therefore,  a  good  plan  is  to  press  out  the  oedema,  either  backwards  under 
the  dorsal  constriction  or  downwards  into  the  preputial  swelling  underneath. 

If  both  these  manoeuvres  fail,  it  is  best  to  employ  the  debridement  method, 
or  to  remove  the  incarcerated  portion  totally. 

The  former  can  be  done,  however  fissured  the  dorsal  constriction  may  be,  and 
even  if  gangrene  has  set  in.  It  is  best  performed  by  retracting  the  skin  of  the  penis, 
and  then  dividing  the  dorsal  constriction  with  a  bistoury  in  the  middle  line.  The 
incision  should  be  from  1  to  1'5  cm.  long,  and  the  depth  can  be  ascertained  by 
the  feel,  as  one  knows  at  once  when  the  fibres  have  been  severed. 

Total  removal  should  be  performed  only  when  there  is  no  fissure,  and  when 
the  area  is  moderately  clean.  The  two  oedematous  preputial  swellings  are  removed 
between  two  parallel  incisions,  and  then  the  edges  are  sewn  together.  This 
operation  produces  a  good  cosmetic  effect,  as  it  obviates  a  chronic  fibrous  swelling, 
which  often  results  from  the  oedema  of  the  basal  portion  of  the  prepuce. 


2g 


CHAPTER  XLI. 

BALANITIS,  CONDYLOMA  ACUMINATUM,  MOLLUSCUM  CONTAGIOSUM, 
HERPES  GENITALIS,  GRANULOMA  INGUINALE,  INDXIRATIO  PENIS 
PLASTICA  AND  PEDICULOSIS  PUBIS. 

Balanitis. 

Simple  balanitis. — Simple  balanitis  is  a  very  common  condition,  and  is  one 
for  which  patients  frequently  seek  advice.  It  is  most  common  in  patients  with 
long  foreskins.  It  often  gives  rise  to  considerable  local  irritation,  and  may  in 
consequence  be  the  cause  of  subsequent  self  abuse.  The  secretion  may  be  even 
sufficient  to  give  rise  to  a  discharge,  and  this  may,  in  its  turn,  set  up  a  urethritis, 
or,  more  often,  may  cause  a  phimosis.  On  withdrawal  of  the  foreskin,  white 
or  yellowish-white  material  will  be  seen,  which  can  be  brushed  away  easily,  and 
which  has  a  peculiar  odour.  This  white  material  usually  goes  by  the  name  of 
smegma,  and  is  supposed  to  be  secreted  by  special  glands,  which  are  called  Tyson's 
glands.  It  is  extremely  doubtful  whether  such  glands  really  exist.  It  is  far  more 
likely  that  it  is  merely  the  sodden  and  desquamating  epithelium  of  the  surface 
of  the  glans  and  the  under  .surface  of  the  prepuce.  In  this  sodden  epithelium,  all 
manner  of  organisms  flourish  ;  urine  collects  in  the  corona  glandis,  and  supplies 
the  pabulum  with  moisture.  The  prodigious  growiih  of  organisms  soon  gives  rise 
to  inflammation,  and  to  the  symptoms  arising  therefrom.  Organisms  which,  under 
ordinary  circumstances,  are  saprophytic,  may  become  pathogenic,  as  such  a  con- 
dition can  be  conveyed  to  a  woman,  in  whom  it  may  set  up  vulvitis  and  urethritis. 
An  analogous  condition  may  occur  in  the  female,  and  it  commences  around  the 
clitoris.  Cleanliness  is  at  once  the  cure  and  the  prevention.  There  can  be  no 
doubt  that  Moses  was  right  in  making  circumcision  compulsory,  and  it  was 
doubtless  his  knowledge  of  the  nmltitude  of  evils  for  which  a  foreskin  may  be 
responsible  that  led  him  to  make  the  law,  which  only  later  developed  a  religious 
significance.  Most  of  the  Jewish  laws  were  primarily  preventive  measures  against 
disease.  It  is  highly  probable  that  pork  was  forbidden  because  of  the  prevalence 
of  trichinosis  in  Palestine,  and  so  on.     Failing  circumcision,  the  foreskin  should 


BALANITIS.  465 

be  withdrawn  daily,  and  the  glans  penis,  sulciiw  coronaiius,  and  the  under  surface 
of  the  prepuce  should  be  well  washed.  Then  the  foreskin  should  not  be  replaced 
until  the  surfaces  have  been  well  dried. 

In  acute  cases  of  simple  balanitis,  a  mild  antiseptic  lotion  should  be  employed, 
and,  after  bathing  the  surfaces  with  it,  an  antiseptic  powder  should  be  used. 

Balanitis  erosiva  et  circinata. — Was  first  described  by  Bataille  and  Berdal,*  *  in 
1889.  The  lesion  commences  as  a  small  circular  greyish-white  patch,  which 
is  merely  the  erosion  of  surface  epithelium.  As  more  epithelium  becomes 
eroded,  the  surface  of  the  lesion  becomes  red,  moist,  and  shiny ;  then  all  the 
lesions  begin  to  coalesce.  The  desquamated  epithehum  collects  in  the  sulcus 
coronarius,  and  quickly  becomes  transformed  into  pus,  which  has  a  charac- 
teristic odour.  The  discharge  is  infectious.  The  organisms  which  cause  this 
condition  appear  to  be  able  to  flourish  only  under  anaerobic  conditions,  since 
it  occurs  only  in  patients  with  foreskins,  and,  if  the  prepuce  is  withdrawn,  the 
lesion  does  not  advance.  Hence  the  best  treatment  is  to  bathe  the  area  with 
nascent  oxygen,  as  may  be  done  by  employing  hydrogen  peroxide  or  perhydrol, 
and  by  leaving  the  wounds  uncovered,  exposed  to  the  air. 

In  severe  cases  in  which  the  foreskin  is  tight,  and  the  discharge  is  fairly 
abundant,  the  prepuce  itself  may  become  eroded,  and  an  inflammatory  oedema 
of  the  prepuce,  leading  to  almost  complete  phimosis,  may  ensue.  In  such  cases 
there  may  be  a  dorsal  lymphangitis  of  the  penis,  with  marked  pain  and  swelling 
of  the  inguinal  lymphatic  glands  ;  but,  oddly  enough,  the  lymphatic  glands  never 
suppurate. 

Occasionally  the  erosions  may  become  ulcers,  and  this  transformation  is  most 
likely  to  be  met  with  in  the  sulcus  coronarius,  and  in  the  neighbourhood  of  the 
froenum.  The  ulcers  are  deep,  the  edges  are  regular,  and  the  base  is  covered 
with  a  diphtheritic-like  membrane  which  is  adherent. 

In  every  case  in  which  ulcers  form,  there  is  always  a  bad  phimosis.  The 
ulcers  may  sometimes  be  found  on  the  under  surface  of  the  prepuce,  and,  at  first 
sight,  resemble  soft  sores.  The  ulcers  in  question  are  more  or  less  funnel-shaped,  and 
the  edges  are  smooth  and  regular — not  irregular  like  the  edges  of  soft  sores. 

In  a  few  cases,  the  ulcers  may  extend  so  rapidly  as  to  perforate  the  prepuce,  and 
even  the  whole  prepuce  may  be  destroyed. 

In  most  of  the  cases,  the  local  pain  is  more  or  less  severe,  and  the  patient 
usually  has  a  rise  of  temperature. 

The  Balanitis  gangrenosa  is  really  the  same  condition  as  the  Balanitis  erosiva, 
with  the  difference  that,  in  the  former,  the  ulceration  is  not  preceded  by  erosions. 
In  Balanitis  gangrenosa,  the  discharge  is,  as  a  rule,  profuse,  and  often  blood-stained, 

2g2 


466  SUBSIDIARY    VENEREAL   DISEASES. 

the  pain  is  very  acute,  and  the  ulcers  are,  as  the  name  implies,  gangrenous,  i.e.,  the 
ulcers  are  surrounded  by  a  dusky-red  zone,  the  edges  are  raised  and  acutely 
inflamed,  and  the  base  is  covered  with  a  yellow,  brown,  greenish,  or  ahnost  black 
diphtheritic  membrane  which  cannot  be  removed.  The  organisms  responsible  for 
this  condition  may  also  be  the  cause  of  a  soft  sore  or  chancre  becoming  gangrenous. 

The  gangrene  may  become  so  extensive  as  to  destroy  the  whole  of  the  penis, 
and  such  a  state  of  affairs  is  often  brought  about  by  the  use  of  strong  disinfectants, 
such  as  carbolic  acid  and  potassium  permanganate.  Almost  any  lotion  other 
than  the  one  specific,  hydrogen  peroxide,  may  aggravate  the  condition.  I  have 
seen  fatal  results  in  two  cases  in  which  carbolic  acid  had  been  used.  In 
both,  the  gangrene  extended  so  rapidly  as  to  involve  the  whole  of  the  scrotum, 
and  it  spread  up  over  the  abdominal  wall  before  any  measure  could  be  taken  to 
check  it. 

An  analogous  condition  to  Balanitis  erosiva  et  gangrenosa  cannot  be  reproduced 
elsewhere,  unless  the  skin  at  the  site  of  inoculation  has  been  badly  injured  and 
in  part  rendered  necrotic.  Therefore,  strictly  sjieakiiag.  Balanitis  gangrenosa  is 
not  autoinoculable,  and  this  point  serves  to  distinguish  it  from  the  soft  sore 
infection. 

Balanitis  erosiva  et  gangrenosa  usually  results  from  coitus,  and  sets  in  about 
2  to  14  days  afterwards.  The  condition  is  due  to  two  organisms  existing  in  a 
state  of  symbiosis.  One  is  a  Gram  positive  vibrio-shaped  organism  which  varies 
from  2-3 "25  fi  in  length;  one  end  is  often  thicker  than  the  other,  and  the  organism 
is  usually  curved.  The  other  organism  is  a  Gram  negative  spirochaeta.  The 
spirochaeta  varies  in  length  from  4-16  /(,  it  is  much  thinner  than  the  vibrio,  it 
stains  violet  with  Giemsa,  and  the  coils  are  very  irregular  ;  in  fact,  there  may  be 
only  one  or  two.  Occasionally,  quite  regularly  coiled  spirochaetae  are  to  be  seen, 
but  the  coils  are  large,  and  never  more  than  five  in  number.  Both  the  spirochaeta 
and  the  vibrio  are  actively  motile,  and  are  indistinguishable  from  the  organisms 
which  cause  Vincent's  angina. 

Clinically,  Balanitis  erosiva  et  gangrenosa  resembles  the  lesions  of  Vincent's 
angina,  and  both  conditions  are  readily  cured  by  salvarsan.  In  my  experience, 
the  condition  is  much  more  common  on  the  Continent  than  in  England. 

In  any  inflammation  of  a  mucous  membrane,  vibrio-shaped  organisms  and 
spirochaetae  can  be  demonstrated,  and,  owing  to  the  numerous  folds  and  crypts 
which  exist  in  the  valva,  vagina,  and  tonsil,  these  organisms  can  flourish 
anaerobically.  A  woman  need  not  necessarily  have  an  acute  vulvitis  or  vaginitis 
to  be  infectious  ;  the  mere  implantation  of  a  few  of  these  organisms  on  a  glans 
penis  which  is  covered  with  a  tight  foreskin  will  be  quite  sufficient  for  the  few 


CONDYLOMA  ACUMINATUM.  -167 

implanted  to  flourish  ou  tlie  desquamated  epithelium,  and  to  reach  the  corona, 
where  the  most  favourable  anaerobic  conditions  prevail. 

I  should  think  it  is  highly  probable  that  a  man  with  a  tight  foreskin 
may  even  develop  this  condition  Avithout  the  infection  coming  from  the 
female — the  starting  point  being  the  irritation  and  slight  inflammation  caused 
by  the  coitus. 

In  the  se^'ere  cases,  the  question  of  operation  often  arises.  Let  me  warn  the 
reader  that,  with  the  exception  of  shtting  up  a  tight  foreskin,  operative  interference 
may  often  do  more  harm  than  good.  The  main  object  must  be  to  keep  the  gan- 
grenous parts  as  dry  as  possible,  and  therefore  after  bathing  them  with  perhydrol 
1  in  20,  some  powder  should  be  applied,  and  the  part  exposed  to  the  air,  or  covered 
up  as  hghtly  as  possible. 

Equal  parts  of  dermatol  and  magnesium  carbonate  (levis)  form  an  efiicient 
dusting  powder.  Magnesium  carbonate  is  used  because  of  its  power  of  absorbing 
moisture.  Magnesium  perhydrol,  or,  as  it  is  sometimes  called,  pergenol,  is  a  useful 
powder  because  it  liberates  oxygen. 

In  closing  my  remarks  on  balanitis,  I  should  like  to  draw  attention  to  one  or 
two  other  points,  which,  although  not  venereal,  may  easily  be  mistaken  for  such. 

Unless  the  diagnosis  is  absolutely  obvious,  it  is  wise  in  cases  of  balanitis  to 
test  the  urine,  as  balanitis  is  not  an  uncommon  complication  of  certain  general 
disorders — for  instance,  diabetes.  Diffuse  lymphogenic  syphilitic  infiltration  of 
the  glans  penis  may  be  mistaken  for  a  simple  balanitis,  but  it  may  readily  be 
distinguished  by  the  violaceous  tint  of  the  organ.  A  syphilitic  balanitis  may  be 
confounded  with  Lichen  'planus  or  psoriasis,  two  diseases  which  not  only  not 
uncommonly  affect  the  glans  penis,  but  also  are  occasionally  limited  to  this  organ. 
Erythema  multiforme  may  cause  a  balanitis  very  difScult  to  distinguish  from  a 
case  of  Balanitis  erosiva,  and,  in  gonorrhoea,  a  circinate  form  of  balanitis  is  not  at 
all  uncommon.  The  gonococcal  balanitis  may  or  may  not  be  a  specific  balanitis. 
If  specific,  it  is  due  to  the  gonotoxine ;  if  not,  it  is  merely  produced  by  the  irritative 
discharge. 

Condyloma  Acuminatum. 

The  terms  venereal  warts  and  gonococcal  warts  are  often  applied  to  this 
condition.  The  lesions  do  not  differ  from  ordinary  warts,  except  that  they  spread 
and  grow  more  rapidly,  and  this  is  simply  due  to  the  moisture  and  warmth  of  the 
regions  in  which  they  occur.  A  wart  is  nothing  more  nor  less  than  a  hypertrophy 
of  epithelium  surmounting  an  inflamed  area  of  corium,  the  blood  supply  of  which 


468  SUBSIDIARY    VENEREAL    DISEASES. 

is  consideiably  increased.  Condylomata  acuminata  may  be  caused  hy  any 
infective  agent,  except  perhaps  the  gouococcus.  The  reason  why  venereal  warts 
are  more  common  in  patients  who  are  or  have  been  suffering  from  gonorrhoea,  is 
simply  due  to  the  fact  that  owing  to  the  discharge  caused  thereby,  saprojihytic 
organisms  can  flourish,  and  it  is  these  saprophytic  bacteria  which  are  responsible. 
Moisture  is  absolutely  necessary  for  the  gi'owth  of  Condylomata  acuminata,  and 
it  is  owing  to  this  fact  that  they  may  sometimes  be  met  with  in  the  umbilicus  and 
the  axillae,  and  the  avoidance  of  moisture  is  the  main  factor  to  be  borne  in  mind 
when  treatment  is  considered.  If  the  area  is  kejit  absolutely  dry,  the  warts  may 
disappear  .spontaneously.  If  there  are  only  one  or  two,  they  are  best  removed  with 
a  Yolkmann's  spoon,  after  being  frozen  with  ethyl  chloride,  and  the  base  should 
then  be  cauterised  with  silver  nitrate  stick  to  stop  the  bleeding.  Condylomata 
in  the  urethra  must  always  be  removed,  as  it  is  impossible  to  keep  the  urethra  dry. 
Large  masses  are  best  bathed  twice  a  day  with  either  a  4  per  cent,  solution  of 
formahn  or  a  2  per  cent,  solution  of  lactic  acid,  then  dried,  and  the  dermatol 
magnesium  carbonate  powder  dusted  on. 

MoLLUSCUM   CONTAGIOSUM. 

Under  this  name  we  understand  papular  lesions  which  vary  from  the  size  of  a 
pin's  head  to  that  of  a  pea.  The  lesions  are  usually  discrete,  non-inflammatory, 
unless  secondarily  infected ;  they  are  whitish  and  waxen  in  appearance ;  they 
are  depressed  in  the  centre,  in  which  there  is  a  httle  plug,  capable  of  being  pressed 
out.  The  matter,  which  can  be  pressed  out,  can  be  examined  without  staining 
under  the  microscope,  and  the  typical  even  sized  and  shaped  degenerated  epithehal 
cells,  characteristic  of  the  condition,  may  be  recognised. 

In  men.  they  are  most  commonly  found  on  the  skin  of  the  penis  and  scrotum  ; 
in  women,  on  the  labia  ;  and  in  children,  on  the  face. 

Occasionally  several  lesions  may  coalesce  and  cover  quite  a  wide  area  with  a 
whitish  waxen  mass,  which  is  raised  above  the  surface  of  the  skin,  is  flat  on  the 
surface,  and  has  little  or  no  inflammation  surrounding  it.  Such  a  condition  is  rncst 
commonly  seen  somewhere  on  the  trunk.  Histologically,  Molluscum  contagiosum 
gives  one  of  the  prettiest  and  most  characteristic  of  pictures,  and  it  is  only 
necessary  to  be  seen  once  to  be  never  forgotten,  and  to  see  it  without  knowing 
it  is  one  of  the  greatest  puzzles. 

The  epithelial  cells  are  the  cells  aSected  ;  they  increase  in  size,  the  nucleus 
swells  and  disappears,  the  nucleoli  first  increase  in  number  and  then  vanish,  so 
that  the  cell,  which  retains  its  outline  almost  to  the  end,  is  filled  with  homogeneous 


MOLLUSCXnH   CONTAGIOSUM    AND    HERPES   GENITALIS.  460 

material  or  debris.  The  epithelial  cells  exhibit  all  the  changes  which  are  to  be 
met  with  in  the  hydrolysis  of  the  protein,  down  to  and  including  the  amino-acid 
stage,  according,  naturally,  to  the  extent  to  which  they  have  degenerated.  The 
different  analytic  products  of  protein  have  different  actions  ;  some  are  basic,  others 
are  acidic,  some  have  a  reducing  action,  others  have  none,  hence  the  reason  why, 
with  almost  any  dye  that  is  used,  the  picture  of  the  epithelial  cells  reminds 
one  of  Joseph's  coat  of  many  colours. 

It  is  highly  probable  that  the  cause  of  Molluscum,  contagiosum  is  an  ultra- 
microscopic  organism,  but  little  is  known  about  it  at  present.  I  have  seen  similar 
bodies  to  those  described  by  Borrel^  and  Lipschiitz,^  ^  but  it  is  practically 
impossible  to  distinguish  them  from  the  debris  in  the  cells,  and  no  reliance  can  be 
placed  upon  the  way  they  stain,  owing  to  the  fact  that  some  of  the  amino-acids 
present  stain  in  the  .same  way. 

The  best  treatment  is  to  remove  the  lesions  with  a  sharp  spoon,  and  to 
cauterise  the  base  with  silver  nitrate. 

If  there  are  several,  and  if  many  have  coalesced,  it  is  best  to  cover  them  with  a 
.strong  salicylic  acid  plaster.  Unna's  salicylic  acid  and  creosote,  or  salicylic  acid 
and  soap  plastermulls  are  very  efficacious. 

Herpes  Genitalis. 

Although  most  common  in  patients  who  have  suffered  from  a  venereal  disease, 
especially  from  gonorrhoea,  it  may  occur  in  thoSe  who  have  not.  The  clinical 
course  of  the  condition  is  nearly  always  unvarying.  The  patient  first  complains  of 
itching,  examines  the  region,  and  finds  a  group  of  tiny  discrete  vesicles  on  an 
inflamed  area.  When  the  vesicles  are  well  pronounced,  as  a  rule  the  subjective 
symptoms  vanish,  and  the  condition  may  spontaneou.sly  disappear,  to  recur  and 
recur,  at  varying  intervals,  later.  On  the  other  hand,  the  vesicles  may  become 
pustules,  and  these  in  turn  become  ulcers.  Several  of  the  lesions  may  coalesce, 
and  the  loss  of  surface  caused  by  them  may  have  an  irregular  outline,  and  may 
closely  simulate  a  soft  sore.  Many  patients  periodically  have  local  pain  and 
itching,  and  all  that  is  to  be  seen  is  a  red  urticarial-like  lesion,  which  vanishes  before 
any  vesicles  appear.  Some  women  have  an  attack  of  herpes  every  time  that  they 
are  unwell. 

In  men,  the  most  common  positions  to  find  herpes  are  on  the  skin  of  the  penis, 
on  the  under  surface  of  the  prepuce,  aird  on  the  glans.  In  women,  herpes  is  most 
frequently  seen  on  both  the  inner  and  outer  surfaces  of  the  labia  majora  and 
minora.  i 


470  SUBSIDIARY   VENEREAL   DISEASES. 

Herpes  genitalis  is  frequently  accompanied  by  aphthoiis  ulcers,  which  are  very 
apt  to  appear  on  a  mucous  membrane  where  there  is  any  irritation  ;  indeed  the 
two  conditions  are  probably  identical.  Irritation  is  the  prime  cause  of  Herpes 
genitalis,  and  the  toxine  which  gives  rise  to  the  irritation  no  doubt  affects  the  sensory 
nerves  peripherally  in  some  way  or  other.  Once  the  latter  are  affected,  the  original 
cause  of  the  irritation  need  not  necessarily  be  repeated,  as  the  patient  being  below 
par  is  sufficient  to  cause  a  recurrence,  and  even  a  dream  often  starts  it ;  so,  too, 
will  an  injection  of  a  gonococcal  vaccine,  or  of  salvarsan. 

The  recurrences  will  often  occur  in  the  same  area,  and  the  site  of  a  chancre  is 
not  at  all  an  uncommon  spot. 

Herpes  genitalis  is  frequently  a  very  troublesome  condition,  as  it  may  cause 
sexual  neurasthenia  (vide  Chapter  XLII). 

Every  case  of  herpes,  in  which  it  is  the  patient's  initial  attack,  must  be  watched, 
as  it  is  sometimes  the  premonitory  sign  of  a  chancre.  Be  herpes  destined  to  be 
followed  by  a  chancre  or  not,  under  no  circumstance  whatever  must  any  irritative 
application  be  used.  Any  form  of  irritation  only  aggravates  the  condition,  and 
it  may  set  up  an  induration  which  is  often  mistaken  by  the  unw"ary  for  a  syphilitic 
lesion.  Herpes  is  certainly  more  common  in  Gentiles  than  in  Jews,  so  we  have 
again  another  indication  for  circumcision.  The  only  treatment  necessary  is  an 
antiseptic  evaporating  lotion,  after  the  application  of  which  a  non-irritating  dusting 
powder  should  be  used. 

Granuloma  Inguinale. 

This  is  a  tropical  disease,  and  it  is  found  most  frequently  in  British  Guiana, 
West  Africa,  South  China  and  Australia.  It  is  occasionally  seen  in  Ceylon,  the 
Malay  Peninsula,  and  Central  Africa.  It  is  highly  probable  that  the  condition  is 
to  be  met  with  in  every  tropical  country.  The  Italians  came  across  it  in  Tripoli.^ 
As  the  disease  more  commonly  affects  women  than  men,  it  is  often  called  Granuloma 
pudendi. 

In  the  female,  the  labia  majora  and  vagina  are  the  parts  first  affected,  then 
the  granulomatous  masses  spread  to  the  mons  veneris,  to  the  genito-crural  folds, 
and  backwards  to  the  anus,  which  they  not  infrequently  surround . 

In  the  male,  the  groins,  prepuce,  glans  penis,  and  the  anus  are  usually  involved. 
The  penis  is  affected  first  of  all.  In  both  sexes,  the  inguinal  lymphatic  glands  are 
enlarged.  The  granulomatous  masses  are  often  accompanied  by  ulcers,  and  it  is 
on  this  account  that  the  condition  is  sometimes  confused  with  the  Ulcus  molle 
serpiginosum.  The  growth  and  rate  of  spread  is  extremely  slow ;  often  a  matter 
of  several  years. 


GRANXJLOMA   INGUINALE.  471 

The  disease  has  a  natural  tendency  to  cure  itself,  but  the  scar  tissue  formed 
is  so  dense,  that  the  cicatrisation  may  be  very  disfiguring. 

The  widest  diversity  of  opinion  prevails  as  to  the  nature  of  the  condition. 
The  disease  is  certainly  infectious  and  auto-inoculable,  and  no  ordinary  remedial 
treatment  appears  to  be  of  much  avail,  although  the  cases  described  in  Tripoli' 
healed  up  with  salvarsan  are  the  only  instances  of  their  kind.  The  best  method 
of  curing  the  disease  is  by  surgical  removal.  Dr.  Wise  has  WTitten  to  me  several 
tunes  from  British  Guiana,  and  he  has  informed  me  that  since  he  has  made  it  a 
rule  to  operate  upon  every  case,  the  disease  is  becoming  rare  in  the  country. 
MacLeod^"  reports  a  case  which  he  cured  with  X-rays. 

Since  the  discovery  of  the  Spirochaeta  pallida,  in  nearly  all  diseases  the 
aetiology  of  which  was  unknown,  spirachaetae  have  been  found,  and  these  have  often 
been  held  to  be  the  specific  organism  by  the  observer.  Granuloma  pudendi  is  one  of 
the  many  instances.  The  extreme  chronicity  of  the  lesion,  and  the  fact  that  salvarsan 
in  the  hands  of  most  observers  has  failed  to  influence  the  condition,  suffices  to  rule 
out  a  spirochaeta  as  being  the  causative  organism. 

Wise,^^  in  1906,  found  some  curious  bodies  to  which  he  refers  as  follows  : — 

"  There  are  present  masses  of  small  bodies  which  seem  to  represent  some  phase 
in  the  life  history  of  a  protozoal  organism.  Stained  by  either  Leishmann's  or 
Giemsa's  stain,  a  thin  capsule  is  apparent  surrounding  a  clear  unstained  space ; 
in  the  middle  of  the  space  is  a  chromatin  staining  curved  rod,  thin  in  the  middle 
and  thicker  club-shaped  at  each  end.  These  bodies  appear  massed  together  in 
numbers  varying  from  2  to  25,  and  are  often  found  within  the  leucocytic  cells 
present." 

Donovan,^^  about  the  same  time,  described  some  intracellular  bodies  which, 
he  said,  looked  like  gigantic  short  bacilli  with  rounded  ends. 

In  1910,  Carter^^  described  a  protozoal  parasite  which  he  found  intracellularly 
situated.  He  says  :  "  The  cytoplasm  of  the  infected  cells  contains  from  15  to  20 
protozoal  parasites  arranged  roughly  in  groups  round  a  central  homogeneous  mass 
simulating  the  zooglia  mass  of  Leishmania  in  cultivation."  Carter  regards  these 
bodies  as  the  gregariniform  stages  of  a  herpetomonas  or  crithidium. 

Steele,  in  Australia,  in  1912,  observed  the  same  bodies  in  large  mononuclear 
leucocytes.  To  this  observer  they  resembled  enlarged  coccobacilli,  sometimes 
kidney-shaped,  not  unlike  huge  gonococci. 

Wise,^^  in  a  later  communication,  in  examining  62  cases,  found  these  bodies 
in  90  per  cent,  of  them.  Many  specimens  he  examined  in  vivo  with  polyclirome 
methylene  blue,  and  what  he  found  is  best  described  in  his  own  words  : — 

"  Careful  observation  reveals  in  the  smallest  of  these  bodies  one  or  two  nuclear 


472  SUBSIDIARY    VENEREAL   DISEASES. 

points  which  later  become  4,  8,  or  12  nuclear  points  ;  finally  in  the  larger  bodies 
12  to  20  nuclear  masses  are  readily  detected.  If  watched  further,  the  proto- 
plasm will  be  seen  to  divide  around  these  nuclear  points  and  form  a  number  of 
spores. 

"  These  spores  when  massed  in  this  way  are  very  noticeable  and  readily  seen. 
They  are  sometimes  present  in  hundreds  all  over  the  specimens.  They  are  very 
beautiful  objects,  in  some  ways  resembling  the  rosettes  of  malarial  parasites  (the 
pigment,  of  course,  being  absent).  The  size  of  each  spore  is  about  2/1000  mm., 
they  are  bronze  coloured,  slightly  pear  shaped,  being  pointed  towards  the  centre 
of  the  rosette  and  arranged  regularly  around  the  centre.  Probably  the  real  position 
of  these  sporulating  bodies  is  within  mononuclear  cells,  but  in  the  scraping  during 
preparation  for  observation,  many  of  the  sporulating  bodies  are  forced  outside  the 
cells  and  broken,  so  that  scattered  fours,  eights  and  twelves  of  these  spores  may 
be  found  extracellularly  situated.  It  is  easy  to  find  six  or  seven  of  these  sporulating 
rosettes  in  a  single  bloated,  tensely-filled  mononuclear  cell.  The  further  stages 
of  existence  as  noted  under  the  microscope,  show  that  the  spores  remain  in  the 
rosette  formation,  but  finally  the  cell  bursts,  or  some  surrounding  invisible  envelope 
bvirsts,  and  the  spores  are  shot  out  into  the  surrounding  plasma.  These  are  non- 
motile,  and  remain  wherever  spread.  Finally  the  slow  dissolution  of  death  steals 
across  their  existence,  the  nucleus  of  the  spore  takes  on  a  curved-rod  shape  slightl}- 
thicker  at  each  end,  the  protoplasm  fades  away  into  a  colourless  indistinct  envelope. 
The  appearance  then  is  exactly  that  which  I  described  in  1906  as  a  thin  capsule 
surroTinding  a  clear  unstained  space  in  the  middle  of  which  is  a  chromatin-stained 
curved  rod,  thin  in  the  middle  and  thicker  club-shaped  at  each  end.  It  would  thus 
appear  that  the  protozoa-like  bodies  seen  in  the  dried  stained  films  are  the  dead 
distorted  remnants  of  a  singularly  beautiful  rosette-like  protozoal  sporulation. 
In  preserving  material  from  Granuloma  pudendi,  death  of  this  parasite  and  the  same 
distorting  processes  occur.  As  by  the  disruption  of  the  protoplasm  the  sole 
colourable  matter  left  is  the  nuclear  particles,  the  detection  of  these  bodies  in  sections 
of  preserved  material  is  rendered  very  difficult,  and  rests  largely  on  the  recognition 
of  the  nuclear  arrangement  in  enlarged  mononuclear  cells. 

"  My  own  experience  shows  that  this  is  difficult,  and  it  is  only  in  well  and  specially 
preserved  material,  stained  carefully,  that  search  is  rewarded.  Carter  found  the 
bodies  with  Giemsa  staining  and  with  eosin  and  methylene  blue  methods.  I  have 
repeated  his  methods  and  have  been  able  to  confirm  his  results.  I  obtain  better 
and  clearer  pictures  with  the  Borrel  staining,  viz.,  rosanilin  hydrochloride  followed 
by  indigo  carmin  and  picric  acid.  I  consider  that  the  peculiar  bodies  described 
in  smears  from  Granuloma  fude^xdi  by  many  observers,  and  occasionally  in  sections. 


Plate  42. 

Section  of  Oranvloma  inguinale  stained  with  pyroiiin  and  methyl  green. 

A.  Intracellular  bacilloid   stage.     A  few   bodies   like   bacilli  are   to   lie 

seen  outside  the  cell,  some  of  which  are  diplococcal  in  form. 

B.  A  further  stage  of  the  preceding,  in  which  the  diplococcal  bodies 

have  increased  in  size. 

C.  A  still  further  stage,  in  which  toui'  bodies  have  been  formed,  every  one 

of  which  is  ready  to  develop  into  two  and  then  into  four  distinct 
bodies. 

D.  A  further  stage  of  the  preceding.     One  body  has  escaped  outside  (K), 

and  the  three  remaining  are   becoming  separated  into  three  anfl 
more  bodies. 

E.  An  escaped  body  from  (D). 

F.  An  escaped  body  from  (C). 

G.  An  embryo  lymphocyte. 


'LATE  42. 


Facing  p.  -172. 


finallv  in  the  !a~2f7 


cells,  but  in  the  sfraping  dHri 

'       I    oi»  illiojiil   oJil  aeibodi   wai  A     .egfila  InoUioBd  ibLjUso^iJiiI  ./ 
.anoi  fir  ljiioooblqi6'9'i.B  rtoJifW'Ib'oHfo'si  .Ilso"  4rlit-  abiyilo  iaida 
Bsibocf  Jido3oo<Jqtb' arfiJ  ddixlw  lii'i.goib^aoiq  l3il*'ldlegfii6'«srf*Ti)liiA;  Iff  in  '■' 

.,    I., If  fiiMli-    i!  -    ■  ;*  1  ';■>;-    i:'    ■  ■■  ,•  .asi«jaib33«3ionc.,9Y£ffj,.  ,,,jvel( 
■mo  yiovo  .bauno^  upail  evad  soibod  iiio\  doiil''  iil  .oiicjg  lodtini  iJit«  A   .0 
tjiiii^il    iiKit  oim  nsdi'  bae  ow*  oirn  for  ei  doidw  lo 

■■'■'■■'■'■•        '*  •■    ■  •'  ■  •  .gaifcod 

.(H)  obiaJiiQ  toq.EOB»  B6d>yi)6d  aaO'   ■.^(nibso^iq  mii  io  e^eis  ledh'^  A.dr 
i<a«  ,99id>t  olii^ .  Ita^jiqaa  gaunqoed,  9T«  ^  giiirii^insi  aavli  adi  bar. 

,  .89ibod  8iom 
(G)'  caoil'i^bocf  baq'fiogs  ah  '.ST 
.(0)  moii  7bod  fesqkoWft/t  !;V 
.3lY^90di(fnyl  ovidrrrainA  iO! 


l*^-'lrV"i^"'^ 


Plate  42. 


GRANULOMA   INGUINALE.  473 

more  particular!)'  by  Carter,  are  really  the  distorted  spores  of  the  asexual  cycle  of 
a  protozoal  parasite. 

"  The  nature  aud  exact  zoological  position  of  the  parasite  remains  the  subject 
of  further  examination.  I  have  found  no  evidence  of  a  crithidial  or  herpetomonad 
origin." 

Wise  then  goes  on  to  note  a  resemblance  of  these  bodies  to  those  which  I  had 
discovered  as  being  the  phases  of  the  life-cycle  of  the  organism  of  syphilis.  Wise 
very  kindly  sent  me  some  material,  and  as  I  have  made  full  use  of  it,  it  would  be 
as  well  to  describe  what  I  found.  Of  course,  I  have  been  unable  to  examine  tissue 
in  vivo  and  have,  therefore,  had  to  rely  upon  fixed  specimens,  and  these  I  have 
submitted  to  the  same  micro-chemical  tests  as  those  which  I  employed  for  the  study 
of  the  Leucocytozoon  st/philidis.  The  bodies  about  to  be  described  are  found  both 
intracellularly  and  extracellularly.  The  former  are  parasitic  upon  the  protoplasm 
of  the  large  mononuclears,  bulging  the  protoplasm  and  pushing  the  nucleus  aside, 
as  is  seen  in  the  intracellular  stages  of  the  Leucocytozoon  syphilidis. 

As  it  is  impossible,  from  fixed  material  alone,  to  work  out  a  life  history,  I  can 
only  describe  the  different  phases  which  I  have  seen  (Plate  42). 

Intracellular  bodies. — («)  In  the  protoplasm  of  a  large  mononuclear  leucocyte, 
tiny  punctate  bodies  are  seen,  and  several  bodies  which  look  like  bacilli.  Most  of 
the  latter  seem  to  occur  in  pairs,  each  lying  parallel  to  the  other.  All  variations 
in  size,  between  the  coccal-like  bodies  and  the  diplobacilli,  are  to  be  met  with,  so 
that  one  is  tempted  to  suggest  that  the  latter  develop  from  the  former. 

(6)  Other  mononuclear  leucocytes  contain  one  or  more  of  these  diplobacilli-like 
bodies.  In  this  case  the  diplobacilli  are  very  much  bigger,  and  they  appear  to  have 
a  capsule. 

(c)  These  diplobacilli-like  bodies  increase  and  increase  in  size,  at  the  expense 
of  the  protoplasm  of  the  leucocyte,  until  a  three  or  four-lobed  body  is  to  be  seen. 
These  latter  are  nuclear  structures,  lying  in  their  own  protoplasm,  which  exists 
in  what  looks  like  an  empty  sack.  The  empty  sack  is  the  remains  of  the  protoplasm 
of  the  leucocyte. 

The  nuclear  bodies  are  either  circular,  horse-shoe,  or  ovoid  in  shape,  and 
sometimes  they  give  the  appearance  of  each  unit's  consisting  of  more  than  one 
part.  The  bacilloid  bodies  are  probably  the  same  as  those  described  by  Siebert^- 
and  Flu." 

Extracellular  bodies. — These  are  obviously  the  same  as,  or  parts  of,  the  intra- 
cellular bodies. 

These  bodies  are  undoubtedly  parasitic  :  they  are  rich  in  nucleic  acid,  and 
the  nuclei  are  surrounded  by  a  resistant  Hpoid-globulin  envelope.     They  give 


474  SUBSIDIARY    VENEREAL   DISEASES. 

exactly  the  same  micro-chemical  tests  as  the  phases  of  the  Leucocytozoon  syphilidis  : 
they  are,  moreover,  optically  active,  and  very  strongly  pyroninophile. 

It  is  highly  probable  that  they  are  protozoal  in  nature,  and  possibly  represent 
the  asexual  stage  of  an  unknown  coccidium.  The  degree  of  resistance  of  the  Upoid- 
globuhn  envelope  to  reagents,  corresponds  with  that  of  the  asexual  phases  of  the 
syphilitic  parasite,  and  is  less  than  that  of  the  gametal  forms. 

That  the  lesion  does  not  usually  clear  up  under  salvarsan,  is  not  against  a 
protozoal  aetiology,  since,  as  the  reader  will  remember,  I  showed  that  when  the 
Leucocytozoon  syphilidis  developed  aberrantly,  salvarsan  did  not  cure  the  lesions 
produced  by  it. 

Induratio  Penis  Plastica. 

Induratio  penis  plastica,  or,  as  it  is  sometimes  called,  van  Buren's  disease, 
although  not  a  venereal  disease,  usually  comes  under  the  observation  of  venereal  and 
genito-urinary  specialists.     Therefore,  I  feel  that  I  ought  to  devote  some  space  to  it. 

Induratio  penis  plastica  is  a  disease  of  unknown  origin,  and  it  appears  to  be 
independent  of  any  local  trouble.  It  begins  as  a  very  gradual  aud  painless 
thickening  of  the  tunica  albuglnea  of  the  corpora  cavernosa.  It  may  occasionally 
begin  in  the  septum,  between  the  two  corpora  cavernosa,  but,  in  either  case,  it  is 
almost  invariably  on  the  dorsum  of  the  penis  that  the  process  takes  place. 

The  condition  is  called  van  Buren's^'  disease,  after  an  observer  of  that  name. 
He  called  attention  to  the  disease  in  America,  in  1874,  but  it  had  been  well  known 
in  Great  Britain  and  on  the  Continent  for  several  years  previously.^^  ^*  '"  ^^ 

Induratio  jyenis  plastica  is  not  a  cavernitis,  and,  therefore,  it  must  not  be  confused 
with  those  hard  nodules  resulting  from  a  cavernitis  of  gonococcal  origin.  S3rphilis, 
trauma,  and,  very  rarely,  leucaemia,  may  give  rise  to  a  dense  cavernitis,  but  it  has 
nothing  to  do  with  the  diseases  mentioned,  and  it  may  be  stated  here  and  now,  that 
Induratio  penis  plastica  is  never  of  venereal  origin,  nor  is  it  secondary  to  any  local 
lesion. 

Generally  speaking,  the  aetiology  is  quite  unknown,  but  in  a  few  cases  the 
condition  is  obviously  a  symptom  of  a  known  and  general  disease  or  diathesis. 

A  large  number  of  the  cases  definitely  suffer  from  gout  and  rheumatism,  others 
have  sugar  in  the  urine,  and,  in  nearly  all,  the  patient  is  over  forty  years  of  age. 
One  of  the  most  extraordinary  points  in  the  disease  is  the  fact  that  the  patient  may 
also  be  suffering  from  a  Dupu}i;ren's  contraction,  and,  if  he  is  not  suffering  from 
it  himself,  a  male  relation  of  his  often  is  a  sufferer.  The  association  with  Dupuytren's 
contraction  is  so  frequent,  that  it  certainly  looks  as  if  Induratio  penis  'plastica  was 
due  to  what  we  loosely  call  a  uric  acid  diathesis  or  arthritism. 


INDURATIO   PENIS   PLASTICA.  475 

Assuming  that  it  is  a  symptom  of  arthritism,  the  question  naturally  arises 
as  to  why  the  penis  in  the  first  place  is  involved,  and,  second,  why  only  a  special 
portion  of  the  connective  tissue  is  affected.  One  is  tempted  to  invoke  the  aid  of 
atavism  in  order  to  find  a  solution,  and  it  will  be  remembered  that  the  so-called 
septum  pectiniforme,  i.e.,  the  septum  between  the  two  corpora  cavernosa,  is  ossified 
in  many  mammals. 

Many  observers  look  upon  Induratio  penis  plastica  as  being  merely  the  extension 
of  a  localised  arteriosclerotic  process. 

Owing  to  the  peculiar  family  history  which  one  gets  in  nearly  all  cases,  history 
of  the  same  condition,  of  Dupuytren's  contraction,  or  of  gout,  it  looks  very  much 
as  if  the  disposition  is  embryonic,  but  what  is  the  cause  of  the  disposition  must  at 
present  remain  a  mystery. 

The  lesion  is  situated  on  the  dorsum  of  the  penis,  by  the  symphysis.  In  its 
early  stage,  it  feels  like  a  nodule  ;  then  this  spreads  superficially,  i.e.,  lengthwise 
and  anteriorly,  until  it  becomes  ribbon-shaped.  The  ribbon  is  thickest  in  the  centre, 
because  of  the  implication  of  the  septum  pectiniforme,  and  its  edges  are  usually 
thin.     It  does  not  become  attached  to  the  skin  above. 

The  ribbon,  though  usually  flat  on  the  surface,  may  occasionally  be  uneven, 
owing  to  there  being  denser  masses  of  fibrous  tissue  in  some  parts  than  in  others. 
The  densest  part  of  the  ribbon  is  the  end  by  the  symphysis,  where  the  growth  starts. 
As  a  rule,  the  patient  is  unaware  of  his  condition  until  he  finds  that  the  penis  has 
a  peculiar  shape  when  erected.  The  kinking  caused  may  prevent  sexual  connection, 
and,  very  often,  from  the  start,  coitus  is  painful,  especially  during  the  act 
of  ejaculation,  owing  to  the  swelling  causing  a  mechanical  narrowing  of  the  urethra. 
The  act  of  micturition  is  never  interfered  with. 

There  is  nothing  characteristic  in  the  pathological  anatomy  of  the  induration. 
The  induration  is  composed  of  fibrous  tissue,  and  the  vessels  in  it  do  not  show  any 
morbid  changes,  hence  the  view,  that  Induratio  penis  plastica  is  only  a  sign  of  a 
general  arteriosclerosis,  cannot  be  held.  Occasionally,  typical  bone  cells  may  be 
found  in  the  tissue.  Treatment  is,  unfortunately,  almost  hopeless.  Some  observers 
state  that  they  have  had  success  with  the  various  methods  which  have,  from  time 
to  time,  been  advocated,  but  most  of  these  I  have  tried  religiously  on  five  patients, 
and  all  without  success. 

Surgical  removal  is  almost  invariably  followed  by  a  recurrence  soon  after  the 
wound  has  healed,  and  there  is  often  a  risk  of  making  the  last  state  worse  than  the 
first. 

Other  local  measures,  such  as  massage,  electric  treatment,  and  ionisation  are 
useless. 


476  SUBSIDIARY    VENEREAL   DISEASES. 

Some  improveiueiit  appears  to  have  followed  vigorous  local  inunction. 
Shillitoe  tells  me  of  a  case  which  he  benefited  with  unguentum  iodex. 

Iodides  internally  appear  to  be  given  by  all  observers,  and  there  is  one  drug 
which  is  specially  in  favour,  namely,  tiodine,  of  which  3  to  6  pills  are  to  be  taken 
daily.  Tiodine  is  an  ethyliodide  compound  of  thiosinamine.  Intramuscular 
injections  of  thiosinamine  and  fibrolysin,  if  the  manufacturer's  reports  are  correct, 
should  certainly  be  prescribed.  Personally,  I  have  had  no  success  with  these 
drugs,  and  on  two  occasions  I  have  observed  severe  toxic  symptoms  to  supervene. 
Fibrolysin  is  merely  a  sodium  salicylate  compoimd  of  thiosinamine. 

Pediculosis  Pubis. 

The  insect,  whose  chief  haunt  is  the  pubic  hair,  is  often  called  the  crab  louse,  or 
Phthirius  inguinalis ;  the  fii'st  word  of  which  is  merely  the  Greek  word  for  a  louse. 

The  Pediculus  pubis  is  much  broader  and  flatter  in  proportion  than  the  other 
pedicuh — indeed  its  body  is  more  or  less  square  shaped.  The  male  is  about 
O'6-l  "0  mm.  in  length,  and  the  female  1  "1-1  '4  mm.  The  terminal  segment  of  the 
abdomen  is  rounded  m  the  male  and  notched  in  the  female.  The  ova  are  about 
10  to  1.5  in  number,  they  are  fixed  to  the  hair  by  a  chitinous  substance,  they  hatch 
out  in  a  week,  and  the  young  are  sexually  mature  in  about  a  fortnight. 

The  pediculi  first  affect  the  pubic  hair  from  which  they  spread  up  the  lateral 
walls  of  the  abdomen  and  thorax  to  the  axillae  ;  they  may  affect  the  whiskers  and 
beard,  and  in  children  they  may  be  found  only  in  the  eyelashes  and  eyebrows.  The 
scalp  is  very  rarely  affected,  but  the  lanugo  hairs  on  the  body  may  be,  in  which  case  the 
most  common  sites  are  the  sternal  region,  the  sacral  region,  and  the  thighs  and  legs. 

As  the  pediculus  is  small,  Ues  flat  on  the  skin  and  looks  Uke  a  little  brown  spot 
when  casually  noticed,  it  is  usually  mistaken  for  a  small  mole,  hence  its  wide  dis- 
tribution is  not  generally  recognised. 

As  a  rule,  the  pediculus  causes  itching,  but  the  pruritus  is  by  no  means  constant. 
If  the  itching  is  intense,  a  pyogenic  dermatitis  usually  results  from  the  continued 
scratching.  Although  it  is  only  in  the  minority  of  cases  that  the  blue  spots 
are  seen,  the  so-called  Maculae  coeruleae  are  absolutely  pathognomonic  of  the 
condition. 

The  Maculae  coeruleae  are  blue,  or  rather  steel-grey  spots,  which  appear  to  be 
slightly  depressed  ;  they  vary  from  the  size  of  a  pin's  head  to  that  of  a  sixpenny 
piece,  and  they  may  be  circular  or  irregular  in  outline.  The  lesions  are,  as  a  rule, 
grouped,  and  are  generally  to  be  found  on  the  antero-lateral  walls  of  the  abdomen 
and  the  sides  of  the  thorax,  or  in  other  words,  along  the  com-se  of  their  journey  from 
the  pubis  to  the  axillae. 


PEDICULOSIS   PUBIS.  477 

The  Maculae  coeruleae  disappear  in  a  week  or  two  after  the  destruction  of  the 
pediculi.  They  are  merely  stains  in  the  skin,  and  the  connection  between  them 
and  Phthirius  inguinalis  was  first  noticed  by  Mourson.-  Duguet,^  by  rubbing  into 
the  skin  an  extract  of  the  pedicuU,  was  able  to  produce  the  lesions. 

Oppenheim^  demonstrated  a  pigment  in  the  bodies  of  the  pediculi,  and  he 
considers  that  the  blue  spots  are  produced  by  a  bite  from  the  insect.  The  bite 
results  in  an  excretion  of  this  coloiu'ing  matter,  this  forms  a  compound  with  the 
haemoglobin,  which  results  in  the  appearance  of  the  blue  spots. 

The  lice  themselves  are  easy  to  kill,  but  the  ova  are  more  difficult  to  exter- 
minate. The  pubis  should  not  be  shaved,  as  the  discomfort  following  the  growth  of  the 
new  hair  is  out  of  all  proportion  to  the  benefit  to  be  derived  from  such  a  measure. 

The  best  method  of  treatment  is  to  spray  the  affected  jjarts  with  96  per  cent, 
alcohol,  and  then  to  rub  in  the  imguentum  hydrarcj.  ammnn.  or  the  plain 
unguentum  hydrarg.  of  the  British  Pharmacopeia. 

A  peculiarity  of  this  form  of  phthiriasis  is,  that  some  individuals  are  much 
more  prone  to  be  affected  than  others,  and  no  prophylactic  measures  appear  to  save 
them.  Hospital  students  sometimes  get  an  attack  whenever  they  return  to  hospital 
after  being  away  for  some  time.  I  know  of  one  case  of  a  medical  student  who  was 
obliged  to  give  up  his  work,  because,  whenever  he  was  at  hospital,  he  used  to  get 
these  lice  all  over  his  body — even  constant  shaving  of  the  pubis  and  axillae  did 
not  save  him. 

'  Duguet  (1880),  "  Gaz.  des  hopit.,"  liii,  362. 

-  Mourson  (1878),  "  Annates  de  Derm,  et  Syph.,"  i.x.  198. 

'  Oppenheim  (1901),  "' Arohiv.  f.  Derm.  u.  Syph.,"  Ivii,  235. 

^  Bataille  et  Berdal  (1889),  "  Compt.-rend  de  la  Soc.  de  Biol.,"  sli,  689. 

5  Berdal  (1897).  "  Traits  des  Malades  Ven."     Paris. 

«  Borrel  (1904),  "  Compt.-rend.  de  la  Soc.  de  Biol.,"  Ivii,  642. 

'  Lipschiitz  (1907),  "  Wien.  klin.  Woch.,"  xx,  253. 

«  Lipschiitz  (1908),  "  Zentralblatt  f.  Bakteriol.,"  xlvi    (orig.),  609. 

'  Sabella  (1913),  "  Giom.  Ital.  d.  Malattie  ven.  c  d.  Pelle,"  liv,  306. 

i»  MacLeod  (1913),  "  Brit.  Journ.  of  Dennat.,"  xxv,  66. 

"  Wise  (1914),  "  Brit.  Guiana  Med.  Annual."     Garden  City  Press,  Letchworth. 

■■-  Siebert  (1908),  "  Archiv  f.  Schifis-  u.  Tropenhyg.,"  xii,  291. 

"  Flu  (1911),  "  Archiv  f.  SchilTs-  u.  Tropenhyg."  (Beiheft  9),  xv.  481. 

'1  Donovan  (1905),  "  Ind.  Med.  Gaz.,"  xl,  414. 

'5  Carter  (1910),  "Lancet,"  i,  1128. 

"=  Wise  (1906),  "  Brit.  Med.  Journ.,"  i,  1274. 

"  van  Buren  and  Keyes  (1874),  "  Xew  York  Med.  Journ.,"  xix,  390. 

'*  Cullerier  (1866),  "  Maladies  Veneriennes,"  p.  72. 

"  Fiirster  (1863),  "  Handb.  d.  spez.  path.  Anatomic,"  2  Aufl.,  s.  372.     Leipzig. 

-■''  Kirby  (1849),  "Dublin  Med.  Press,"  xxii,  210. 

-'  MacClellan  (1828),  "  Journ.  univ.  des  scienc.  nied.,"  xlix,  340. 


CHAPTER  XLII. 
SEXUAL    NEURASTHENIA. 

There  are  three  kinds  of  sexual  neurasthenia  :  (1)  the  form  that  occurs  in 
patients  who  have  never  had  a  sexual  disease  ;  (2)  the  form  that  occurs  in  patients 
who  have  had  gonorrhoea ;  (3)  the  form  that  occurs  in  patients  who  have  had 
sj^hilis. 

The  fornr  of  sexual  neurasthenia  which  is  sometimes  met  with  in  patients  who 
are  continually  suffering  from  recurrences  of  Herpes  genitalis,  is  usually  the  same 
as  that  form  which  follows  gonorrhoea.  Herpes  genitalis  cannot  strictly  be  called 
a  sexual  disease,  in  the  light  in  which  we  regard  gonorrhoea  and  syphilis,  but  as 
most  of  the  cases  have  had  gonorrhoea,  it  is  always  wise  thoroughly  to  examine 
every  neurasthenic  who  complains  of  frequent  attacks  of  Herpes  genitalis,  so  as 
to  see  if  he  has  a  chronic  prostatis  or  spermatocystitis.  Patients  who  suffer  from 
sexual  neurasthenia,  but  who  have  never  had  a  sexual  disease,  are,  as  a  rule, 
patients  particularly  deficient  in  intellect  or  effeminate,  or  those  who  have  especially 
given  way  to  self-abuse  in  their  early  youth.  Such  patients  either  complain  of 
constant  nocturnal  emissions,  or  that  they  cannot  perform  the  sexual  act. 

Those  who  complain  of  the  former,  are  generally  men  between  20  and  30  years 
of  age,  men  who  have  to  work  hard  in  a  stuffy  office,  who  can  get  but  little  exercise, 
and  who  have  their  meals  irregularly,  and  not- good  ones  at  that.  They  come  home 
brain-fagged  but  not  bodily  fagged,  and,  having  had  little  or  no  exercise,  they  feel 
the  cold  very  much,  with  the  result  that  they  load  their  beds  with  heaps  of  clothes. 
A  too  warm  bed  is  a  very  frequent  cause  of  nocturn&,l  emissions.  These  patients 
will  not  infrequently  tell  you  that  they  suffer  from  nocturnal  emissions  much  more 
frequently  when  they  lie  on  their  backs  than  on  their  sides,  and  when  the  head  is  not 
well  raised  above  the  rest  of  the  body. 

These  patients  are  almost  invariably  very  constipated,  and  not  infirequently 
they  have  a  varicocele.  A  great  deal  can  be  done  by  hygienic  treatment  for  this 
class  of  case.  If  the  patient  has  a  varicocele,  he  should  wear  a  suspensory  bandage, 
the  bowels  should  be  piit  in  order,  meals  should  be  taken  at  regular  intervals,  and 


SEXUAL   NEURASTHENIA.  479 

a  carbohydrate  diet  should  be  avoided.  A  little  red  wine  is  beneficial,  but  malt 
liquors  should  not  be  taken.  Tonics  containing  strychnine,  iron,  arsenic,  and 
phosphoric  acid  shoidd  be  prescribed.  The  patient  should  be  advised  to  take  a 
certain  amount  of  exercise  every  day  ;  he  should  not  go  to  bed  for  three  or  four 
hours  after  his  dinner,  nor  have  a  nightcap  of  whisky  and  soda,  nor  have  too  many 
clothes  on  his  bed  ;  he  should  have  a  pillow  and  a  bolster,  or  two  pillows,  and  his 
wndows  should  be  wde  open,  winter  and  summer  alike.  A  great  deal  can  be  done 
by  an  occasional  talk  with  the  patient,  and  it  is  a  good  plan  to  urge  him  to  take 
up  a  hobby,  and,  in  all  cases,  the  literature  he  reads  should  be  considered  by  the 
physician  in  charge.  Even  medical  men  are  inclined  to  ridicule  the  condition. 
Those  who  do,  little  know  what  a  serious  condition  it  is;  it  is  a  disease,  and  should 
be  regarded  as  such.  There  can  be  little  doubt  that  there  is  a  lesion  somewhere 
which  we  are  not  advanced  enough  to  detect,  but  the  fact  that  it  is  hidden  does  not 
warrant  us  in  assuming  that  there  is  nothing  wrong.  I  mention  this  particidarly, 
because  the  sweating  and  mode  of  living  of  a  large  proportion  of  the  population,  in 
big  cities,  is  very  conducive  to  this  form  of  sexual  neurasthenia.  The  disease  is 
undoubtedly  on  the  increase,  the  "  World  War  "  is  certain  to  aggravate  it,  and 
those  who  are  accustomed  to  see  cases  know  well  what  havoc  it  can  play  with  a 
man's  life. 

Those  patients  who  complain  that  they  cannot  perform  the  sexual  act,  if  they 
have  had  no  venereal  disease,  are  generally  men  who  may  be  said  to  have 
passed  the  sexual  period,  or  men  who  have  an  enlarged  prostate,  or  men  who  have 
lived  in  tropical  climates.  Other  causes  are  alcohol,  and  more  or  less  sudden 
adiposity.  In  spite  of  the  literature,  and  of  the  manifold  ''tips"  which  are  widely 
circulated  in  all  Continental  cities,  there  is  no  cure  whatever  for  this  condition. 
Aphrodisiacs,  such  as  damiana,  muiracethin,  yohimbin,  etc.,  and  the  various  forms 
of  electrical  treatment  and  appliances  which  are  advocated,  are  useless.  It  is  the 
duty  of  the  physician  to  explain  to  the  patient  that  the  condition  is  a  physiological 
one,  and  that  he  must  make  the  best  of  what,  perhaps,  may  be  to  the  patient  a  bad 
job.  I  had  one  very  interesting  case,  in  which  a  man,  aged  39,  consulted  me  re 
the  question  of  marriage.  For  the  last  two  years  he  had  been  unable  to  have 
sexual  connection,  as  he  could  not  get  an  erection.  Three  years  ago,  the  patient  had 
a  bad  attack  of  blackwater  fever  in  the  Gold  Coast,  and  ever  since  his  convalescence 
he  had  been  gradually  putting  on  weight,  so  that  he  w^eighed,  when  I  first  saw  him, 
19  stone,  his  previous  weight  having  been  only  12  stone.  In  spite  of  reducing  his 
weight  somewhat  with  careful  exercise,  massage,  and  the  administration  of  thyroid 
extract,  the  patient  has  never  been  able  to  get  an  erection.  Since  then  I  have 
seen  other  cases  of  adiposity,  which  were  accompanied  by  a  loss  of  sexual  function. 

2h 


480  SEXUAL   NEURASTHENIA. 

If  the  patient  has  had  syphilis,  and  is  on  the  right  side  of  45,  a  loss  of  sexual 
function  generally  signifies  that  he  has  a  degenerative  myelitis.  As  in  many  cases 
of  degenerative  myelitis  there  is  no  history  of  syphilis,  it  is  always  wise  to  bear 
this  trouble  in  mind,  if  a  patient  seeks  advice  for  loss  of  sexual  power.  Another 
very  common  cause  of  sexual  neurasthenia  is  coitus  intenuptus,  a  continued  practice 
of  which  may  even  lead  to  dementia. 

The  gonorrhoeal  form  of  sexual  neurasthenia  is  quite  different  from  the  syphilitic 
form.  In  the  former,  the  patient  usually  has  a  gonococcal  lesion,  and  the  neuras- 
thenia is  doubtless  a  toxic  manifestation  of  the  disease.  In  the  latter,  the  patient 
is  either  cured  of  his  syphilis,  or  he  has  never  had  syphilis,  but  imagines  that  he 
has  had  it.  Putting  aside  for  a  moment  the  neurasthenia  which  patients  are  liable  to 
get  when  they  first  get  syphilis,  and  know  that  it  is  syphilis  that  they  have  got,  I 
have  only  seen  one  case  in  which  syphilitic  neurasthenia  occurred  in  a  patient  with 
an  active  lesion,  and  then  it  was  a  symptom  of  degenerative  encephalitis,  from 
which  he  ultimately  died. 

Syphilitic  neurasthenia  is  not  due  to  the  toxine  of  the  syphilitic  organism, 
because  toxines  do  not  play  a  marked  role  in  protozoal  diseases,  because  the  type  of 
neurasthenia  is  seen  in  patients  who  have  never  had  syphilis,  because  I  have  seen 
very  bad  cases  in  which  the  patient  never  had  more  than  the  primary  sore,  as  the 
treatment  was  begun  early,  and  because  extraneous  catastrophes  often  bring  it  on 
or  aggravate  it.  Syphilitic  neurasthenia  is  very  apt  to  affect  patients  who  have 
had  an  attack  of  neurasthenia  before,  patients,  one  can  say,  who  have  a  mental 
family  history. 

The  "  World  War  "  has  been  a  potent  cause  of  syphilitic  neurasthenia,  as  well 
as  every  other  form  of  neurasthenia  ;  indeed,  it  has  caused  a  neurasthenia  of  its 
own. 

None  of  these  factors  affect  gonorrhoeal  neurasthenia,  therefore,  in  mj'  opinion, 
gonorrhoeal  nem'asthenia  is  a  true  toxic  manifestation  of  the  disease,  since  it  often 
disappears  when  the  patient  is  cured,  while  syphilitic  neurasthenia  does  not  differ 
from  an  ordinary  neurasthenia,  except  in  so  much  as  it  is  the  idea  of  the  syphilis 
which  has  started  the  ball  rolling,  in  a  patient  who  is  normally  unstable  or  mentally 
weak.  Syphilitic  neurasthenia  does  not  differ  from  war  neurasthenia,  hence  neither 
the  cure  of  the  syphilis  nor  the  cessation  of  the  war  would  cure  the  patient. 

We  will  first  of  all  discuss  the  gonorrhoeal  neurasthenia.  The  symptoms 
complained  of  vary,  but  they  may  all  be  described  as  disturbances  of  the  sexual 
function.  The  sexual  desire  may  be  abnormally  augmented,  or  the  patient 
may  be  impotent.  Patients  frequently  complain  of  what  they  commonly  call 
sexual  weakness,  that   is.   inability   to  get   full    erections,   ejaculatio   ■praecox,   loss 


SEXUAL   NEURASTHENIA.  48  i 

of  sensation,  or  even  extreme  pain,  just  prior  to  and  during  the  ejaculation. 
Patients  frequently  note  that  the  amount  of  seminal  fluid  passed  is  very  small. 
Some  patients  complain  bitterly  of  prostatorrhoea,  which  they  always  mistake 
for  spermatorrhoea ;  and  the  constant  passage  of  what  they  think  to  be 
their  semen,  which  they  usually  seem  to  look  upon  as  part  of  their  spinal  cord, 
has  a  most  baneful  influence  on  their  mental  condition.  The  symptoms  just 
mentioned,  which  are  typical  of  gonorrhoea!  neurasthenia,  are  also  the  symptoms 
of  a  chronic  inflammation  of  the  coUiculus,  the  prostate,  and  the  vesiculae  seminales. 
The  great  pain  sometimes  complained  of,  prior  to  and  during  the  seminal  ejaculation, 
is  due  to  a  narrowing  or  closure  of  the  ejaculator}-  ducts,  or  of  some  of  the  ducts  of 
the  prostate,  hence  in  these  cases  the  amount  of  seminal  fluid  passed  is  often  far 
below  the  normal. 

Once  a  patient  begins  to  worry  about  these  symptoms,  he  quickly  loses  weight, 
is  usually  constipated,  and  complains  of  headaches,  vague  pains  over  the  body, 
indigestion,  and  inability  to  work  or  sleep. 

Some  patients  who  have  been  under  treatment  for  some  time,  and  who  look 
upon  gonorrhoea  as  an  incurable  disease,  or  with  as  much  awe  as  syphilis  is  commonly 
regarded,  are  naturally  apt,  if  their  mental  balance  is  not  properly  adjusted,  to 
develop  a  form  of  neurasthenia  indistinguishable  from  that  met  with  in  syphilis. 
Theso  are  patients  who  would  have  developed  neurasthenia  on  any  very  strong 
provocation,  and  the  only  way  to  treat  them  is  by  suggestion. 

Because  a  patient  has  gonorrhoeal  neurasthenia,  it  must  not  be  hastily  assumed 
that  he  has  an  active  gonococcal  lesion,  since  the  prostatitis,  or  whatever  organ 
it  is  that  is  affected,  may  be  kept  up  by  a  secondary  infection,  and  this  may  keep 
the  neurasthenia  going.  That  gonorrhoeal  neurasthenia  may  be,  and  is  often 
met  with  long  after  all  gonococci  have  vanished,  might  throw  doubt  upon  the 
gonotoxic  origin  of  it. 

Not  at  all.  Herpes  genitalis  is  a  very  frequent  gonotoxic  symptom,  but, 
nevertheless,  the  condition  may  go  on  recurring  and  recurring  long  after  the 
gonorrhoea  has  been  cured  and  forgotten.  Take  again  a  syphilitic  neuritis.  Once 
the  sensory  fibres  have  been  affected,  in  spite  of  treatment  and  the  disappearance 
of  the  syphilitic  process,  pains  and  other  symptoms  may  still  persist. 

In  cases  of  gonorrhoeal  neurasthenia,  it  is  necessary  to  find  out,  first  of  all,  if 
the  lesion  of  the  prostate  or  seminal  vesicles  is  still  due  to  the  gonococcus,  or  to  a 
secondary  infection. 

If  due  to  the  gonococcus,  the  patient  should  be  treated  according  to  the  trouble 
found,  and  should  be  under  vaccine  treatment  for  about  six  or  nine  months.  Such 
a  course  usually  suffices  to  cure  the  case.     If,  on  the  other  hand,  no  gonococci  are 

2h  2 


482  SEXUAL   NEURASTHENIA. 

found,  and  it  is  tolerably  certain  that  a  secondary  infection  persists,  the  patient 
should  be  treated  on  hygienic  lines,  and  by  suggestion.  Cold  applications  to  the 
prostate  by  means  of  the  psychrophore  often  do  a  great  deal  of  good,  and,  in  very 
obstinate  cases,  it  might  be  advisable  to  treat  the  patient  with  a  mixed  autogenous 
vaccine  made  from  his  prostatic  secretion.  In  these  cases,  instrumentation  of  the 
urethra,  and  the  injection  of  antiseptics  should  be  avoided  as  far  as  possible. 

It  is  a  very  odd  fact  that  many  patients  with  gonorrhoeal  nem'asthenia  develop 
— when  the  neurasthenic  symptoms  appear — phosphaturia,  oxaluria,  or  uraturia. 
The  thickness  of  the  urine  caused  by  these  salts  is  often  a  very  great  source  of  worry 
to  the  patient,  and,  of  course,  an  excess  of  crystals  in  the  urine  is  apt  to  aggravate 
any  chronic  inflammation  of  the  prostate.  As  so  many  of  the  other  symptoms 
of  gonorrhoeal  neurasthenia— such  as  the  neuralgic  pains,  errors  of  digestion, 
chronic  constipation,  cardiac  neuroses — are  suggestive  of  an  affection  of  the 
sympathetic  nerves,  it  is  possible  that  the  polyuria,  phosphaturia,  etc.,  is  also  a 
sympathetic  nerve  disturbance.  Although  the  hypochondria  which  sometimes 
accompanies  gonorrhoeal  neurasthenia  is  not,  as  a  rule,  so  severe  as  that  that 
follows  syphilitic  neurasthenia,  it  should  not  be  forgotten  that  several  cases  have 
been  known  to  commit  suicide. 

Syphilitic  Neurasthenia. 
The  type  of  person  usually  affected  with  this  form  is  mentally  weak,  conscientious 
in  his  work  and  habits,  and  one  who  has  always  had  an  awful  di-ead  of  catching 
syphilis.  Consequently,  such  patients  come  for  advice  very  early,  and  therefore 
they  can  generally  be  cured,  before  they  develop  any  further  manifestations  of 
the  disease.  In  spite  of  being  cured,  and  in  spite  of  what  you  tell  them,  this  class 
of  patient  cannot  be  convinced.  They  may  even  realise  that  they  are  foohsh,  and 
they  may  be  impressed  for  the  moment  by  the  rosy  picture  painted  for  them ; 
but,  on  leaving  the  source  of  comfort,  they  recede  to  their  melanchohc  state.  The 
worst  cases  commit  suicide.  I  have  been  unfortunate  enough  to  have  had 
two  such  cases.  Both  these  cases,  and  milder  ones  which  I  have  had,  I  have 
sent  on  to  physicians  who  practise  psychotherapy,  but  I  have  never  yet  seen 
a  case  which  has  been  cured  by  hypnotism  or  suggestion.  Not  all  these  cases  have 
the  same  ideas.  Some  imagine  that  they  cannot  be  cured,  and  that  they  will 
ultimately  become  mad  through  the  syphilis.  Others,  on  the  other  hand,  imagine 
that  they  are  a  continual  source  of  infection  to  others.  One  of  my  cases — who 
terminated  his  own  existence — first  imagined  that  he  had  infected  all  his  relations. 
To  please  him,  I  saw  his  relations  in  turn,  and  tried  to  convince  him  that  his  idea 
was    foolish.      He    next  said  that  anyone  who  passed  him  in  the  street  became 


SEXUAL   NEURASTHENIA.  483 

infected,  and  he  would  often  cross  over  on  to  the  other  side,  to  avoid  them.  He 
was  so  perturbed  at  thinking  he  had  infected  so  many  people,  that  he  never  went 
about  without  a  pistol  in  his  pocket,  as  he  expected  any  moment  that  one  of  his 
victims  would  shoot  him  in  the  back.  When  I  suggested  to  him  that  he  did  not 
appear  to  mind  whether  his  frequent  visits  to  me  infected  me  or  not,  he  imagined 
that  I  could  protect  myself  and  all  those  around  me.  He,  moreover,  accused  me 
of  not  protecting  all  those  whom  he  had  already  infected.  This  man  ended  his  life 
by  cutting  his  throat. 

Syphilitic  neurasthenia  is  on  the  increase.  Life  being  more  strenuous  and 
more  of  a  bustle,  especially  in  densely  populated  cities,  than  it  was,  is  one  of  the 
causes.  The  more  ready  access  which  patients  have  to  medical  literature,  and  the 
intelligent  interest  that  a  very  large  proportion  of  the  lay  public  take  in  matters 
medical,  is  another  cause.  The  lay  Press  has  recently  allowed  a  few  words  con- 
cerning the  disease  to  appear  in  its  columns.  The  way  these  words  are  veiled,  the 
peculiar  heading  that  is  attached  to  them — "  Hidden  Plague  " — defeats  its  purpose, 
and  is  enough  to  put  the  fear  of  God  into  anyone.  All  deaths  from  salvarsan,  upon 
which  there  is  an  inquest,  find  their  way  into  the  papers.  The  patient  is  said  to 
have  died  from  arsenical  poisoning,  which,  of  course,  is  absolutely  untrue. 

The  number  of  cases  of  blindness  following  salvarsan,  which  have  appeared  in 
the  Daily  Press,  is  legion.  What  effect  must  this  have  on  a  neurasthenic  youth? 
In  the  first  place,  the  syphilis  makes  him  look  upon  himself  as  a  leper ;  he  regards 
the  disease  as  incurable,  and  he  makes  up  his  mind  that  he  is  going  to  develop 
syphilitic  madness.  In  the  second  place,  he  dare  not  have  salvarsan,  for  fear  it  is 
going  to  kill  him  or  make  him  blind.  This  line  of  argument  is  a  very  common  one 
with  patients,  and  is  one  of  the  reasons  why  they  first  consult  a  druggist  or  a  quack, 
because  they  know  they  will  be  told  that  the  sore  is  onh'  a  chafe. 

The  "World  War  "  is  a  very  fruitful  cause  of  syphilitic  neurasthenia,  and  I  have 
already  seen  a  few  cases,  the  symptoms  being  of  this  nature.  The  patient  dare  not 
go  to  a  Recruiting  Office  for  fear  the  examining  doctor  may  perceive  that  he  has  had 
syphilis,  and  he  dare  not  go  about  the  streets  in  daylight,  for  fear  of  being  scoffed 
at  for  not  joining  the  Colours.  These  two  points  weigh  so  much  upon  the  patient's 
mind  as  almost  to  drive  him  mad. 

The  type  of  man  who  used  to  commit  suicide  when  he  knew  that  he  had 
contracted  syphilis,  fortunately  is  not  met  with  nowadays.  The  man  was  not  a 
neurasthenic,  but  simply  committed  suicide  to  save  himself  the  horror  and  misery 
of  being  an  invalid  for  the  rest  of  his  life,  and  then  ending  it  in  a  madhouse.  This 
type  of  man  is  open  to  reason,  and,  once  he  is  told  that  he  can  be  cured,  he  no  longer^ 
worries.     A   strong,    healthy   looking   man   with    early   generalised   syphilis   once 


484  SEXUAL   NEURASTHENIA. 

consulted  me.  His  first  question  was,  Have  I  syphilis  ?  His  second  question 
was,  Can  I  be  cured?  He  afterwards  informed  me  that,  if  I  had  not  answered  his 
second  question  in  the  afErmative,  he  would  have  done  away  with  himself. 

Every  venereal  patient  should  be  looked  upon  as  a  special  sort  of  individual, 
and  the  physician  in  charge  should  always  adopt  a  most  optimistic  tone.  The 
knowledge  that  many  patients  have  of  medical  science  is  often  much  greater  than 
that  with  which  they  are  accredited,  so  that,  in  any  suspicious  patient,  I  have 
always  found  it  to  be  a  good  plan  to  let  him  follow  my  line  of  argument,  and  to  tell 
him  the  reason  why  so  and  so  many  injections  are  given,  and  why  the  treatment 
is  continued  for  so  and  so  long.  When  the  position  is  laid  before  them,  they 
naturally  ask  questions,  the  answers  of  which  can  always  be  true,  and  3'et  be  quite 
optimistically  painted.  Answers  to  questions,  put  to  you  by  a  patient,  penetrate  far 
deeper  into  the  patient's  mind  than  all  the  talk  in  the  world  from  the  doctor.  The 
present-day  patient  is  flattered,  when  the  physician  takes  him  into  his  confidence 
and  explains  to  him  the  rationale  of  every  step  he  takes.  For  the  bad  cases  of 
syphilitic  neurasthenia  one  certainly  can  do  nothing.  Mild  cases  can  often  be 
cured  in  time,  and  any  number  of  susceptible  patients  can  be  prevented  from 
developing  neurasthenia,  if  they  are  dealt  with  as  I  have  described  above.  Con- 
sidering that  neurasthenia  is  such  a  common  disease  of  the  female  sex,  it  is  an  odd 
fact  that  one  seldom  sees  a  case  of  sexual  neurasthenia,  i.e.,  neurasthenia  caused 
by  either  gonorrhoea  or  syphilis,  in  a  woman. 


CHAPTER  XLIII. 
VENEREAL  DISEASE  AND  MARRIAC4E. 

Syphilis. 

All  authors,  in  discussing  the  question  of  syphilis  and  marriage,  have  hitherto 
pinned  themselves  down  to  a  time  limit.  For  instance,  Hutchinson^  said 
that  a  man  might  marry  with  safety,  if  he  had  continued  treatment  for  two 
years  from  the  date  of  his  chancre.  Fournier-  said  that  four  or  five  years 
should  elapse,  and  most  other  authors  more  or  less  echo  Fournier's  views. 
When  either  the  cause  of  syphihs  was  unknown,  or  was  thought  to  be  only 
the  Spirochaela  j)allida,  theoretically  it  would  have  been  justifiable  to  fix  a  time 
limit,  and  still  greater  would  this  justification  be,  now  that  salvarsan  has  seen 
daylight,  for  the  simple  reason  that  we  are  told  that  all  the  spirochaetae  in  the 
body  are  killed  by  this  drug.  I  cannot  help  thinking  that  all  authors  who  have 
advocated  a  time  limit  have  done  so  on  theory  alone,  and  have  not  allowed  their 
clinical  experience  to  influence  them.  My  own  clinical  experience  is  not  so  great 
as  that  of  Hutchinson,^  Fournier,^  Gougerot,^  and  some  of  the  other  writers 
on  this  subject  whom  I  have  in  mind,  but  yet  I  have  learnt  that  a  time  limit  is  futile 
and  untrustworthy. 

The  reader  will  see  later  on,  from  the  cases  I  am  bringing  forward,  and  from 
the  previous  pages,  that  the  Spirochaeta  pallida  cannot  be  the  actual  cause 
of  the  disease  itself,  but  that  some  other  phase  or  phases  must  exist,  which  can 
lie  dormant  for  an  indefinite  period,  and  then  re-awaken  and  cause  symptoms  again. 

The  spore  is  the  dormant  phase ;  it  is  the  actual  cause  of  the  disease,  and  it 
may  lie  dormant  in  any  part  of  the  body,  without  causing  any  disturbance  of  the 
host's  cells  in  the  locality  in  which  it  is  situated. 

Although  it  may  lie  dormant,  it  may  re-awaken  and  give  rise  to  other  phases 
which  will  cause  symptoms,  or  it  may  never  re-awaken  until  it  gains  entrance  to 
a  new  host,  hence,  if  a  patient  is  harbouring  spores,  he  is  harbouring  a  potentially 
harmful  infective  agent. 

If  the  spore  remains  dormant  for  a  sufficiently  long  time,  the  host  will  cease  to 


486  EUGENIC   ASPECT   OF    VENEREAL   DISEASE. 

form  protective  bodies ;  but  the  fact  that  the  Wassermann  reaction  is  negative, 
is  no  proof  tliat  the  patient  is  not  harbouring  the  infective  agent. 

Many  individuals — and  I  am  inclined  to  believe  that  the  kind  of  infection 
plays  a  role — will,  pro\'ided  the  organisms  have  been  present  for  a  certain  period 
(the  period  varies  enormously  in  different  persons),  continue  to  form  protective 
bodies  long  after  the  organisms  have  been  killed.  Therefore,  because  a  patient 
gives  a  positive  Wassermann  reaction,  it  does  not  necessarily  follow  that  he  has 
active  syphilis,  and  so  must  not  consider  himself  a  candidate  for  marriage. 

As  far  as  we  can  see  then,  at  present  it  would  appear  that  neither  by  clinical 
nor  by  pathological  means,  can  we  say  for  certain  when  a  patient  may  marry  without 
risk.  Tf  we  go  more  carefully  into  the  matter,  and  bring  every  point  into  con- 
sideration, we  can  be  more  definite  than  this.  S^^hilis  in  the  man  will  be  dealt 
with  first. 

If  a  man  has  been  put  under  treatment  before  he  has  reached  the  generalisation 
stage,  and  provided  that  treatment  has  been  adequate,  he  can  maiTy  at  any  time. 

I  should  consider  four  to  five  consecutive  injections  of  salvarsan  or  neo-salvarsan 
and  mercury  for  a  year,  to  be  adequate  treatment. 

In  such  an  early  case  as  this,  a  Wassermann  reaction  would  be  of  value,  since, 
if  a  positive  result  were  obtained,  it  would  obviously  mean  that  the  patient  had 
entered  the  generalisation  stage  while  under  treatment.  Such  a  thing  is  possible, 
but  fortu2iately  it  very  seldom  occurs. 

Case  77. — I  was  consulted  by  a  man  ^ith  a  primary  sore  on  the  corona,  and 
the  sore  could  not  be  removed.  The  Wassermann  reaction  was  negative,  both 
before  and  directly  after  treatment  was  inaugurated.  I  gave  him  five  injections  of 
neo-salvarsan,  allowing  four  days  to  elapse  between  each  pair  of  injections.  As  he 
had  to  leave  England  almost  immediately,  he  was  obhged  to  take  mercury  internally, 
and  so  could  not  have  intramuscular  injections.  I  saw  him  again,  nine  months 
later,  when  he  presented  mucous  papules  in  his  mouth,  a  general  adenitis,  and  a 
positive  Wassermann  reaction.  He  also  informed  me  that  the  site  of  his  primary 
sore  had  swollen  up  and  had  become  very  red  a  month  or  two  previously. 

To  make  absolutely  sure  that  a  case  is  cured,  a  provocative  injection  of  salvarsan 
may  be  given,  and  the  patient  may  be  passed,  if  the  blood  test  is  negative  before, 
and  forty-eight  hours  after,  the  injection.  If  the  provocative  injection  is  to  be 
given,  it  must  be  ascertained  that  the  patient  has  had  no  treatment  for  six  months. 

Speaking  broadly  then,  if  a  patient  has  been  put  under  treatment  before  he 
has  reached  the  generalisation  stage,  he  may  marry  without  risk. 

If  treatment  is  not  begun  until  the  generalisation  stage  has  been  reached, 
provided  the  patient  has  had  about  nine  injections  of  salvarsan  and  thorough 


MARRIAGE.  487 

mercurial  treatment  for  two  years,  the  risks  of  his  infecting  his  wife  are  small,  but 
they  exist  theoretically.  I  have  actually  seen  such  recurrences,  although  I 
have  never  known  of  an  infection  of  another  party. 

If  only  two  or  three  injections  of  salvarsan  have  been  given,  and  even  if  mercury 
is  prescribed  for  two  years,  the  risks  are  certainly  much  greater,  as  I  have  already 
seen  ten  cases  in  which  a  wife  has  become  infected.  These  cases  had  all  been 
treated  by  other  men,  and  they  came  to  me  because  of  what  had  occurred.  It  is 
therefore  possible  that  my  failures  have  also  gone  elsewhere.  I  do  not  think  that 
this  explanation  is  the  correct  one,  otherwise  many  articles  would  have  appeared 
in  the  medical  journals,  to  the  effect  that  the  treatment,  even  with  several  injections 
of  salvarsan  and  mercury  for  two  j'ears,  does  not  cure  syphilis.  The  treatment 
which  I  have  advocated  for  the  past  four  years  is,  I  think,  generally  considered,  in 
this  country,  to  be  unnecessarily  severe.  I  am  quite  positive  that  recurrences  are 
far  more  freqiient  when  only  two  or  three  injections  are  given  at  first,  than  when 
nine  are  prescribed,  therefore  I  think  I  am  probably  right  in  assuming,  that  a  man 
who  has  been  treated  in  the  latter  way  is  a  better  candidate  for  marriage  than  one 
who  has  undergone  the  former  treatment. 

Once  a  patient  has  reached  the  generalisation  stage,  spores  may  have  settled 
in  any  corner  of  the  body,  and,  being  only  potentially  harmful,  neither  a  Wasser- 
mann  reaction  nor  a  provocative  injection  at  a  later  date  will  give  results  from 
which  an  absolutely  trustworthy  statement  re  a  cure  can  be  made.  Here,  again, 
we  can  be  more  exact,  since  it  \vill  naturally  depend  upon  how  long  the  patient 
has  been  in  the  generalisation  stage.  The  shorter  the  time,  the  greater  the  value 
of  a  Wassermann  reaction  and  a  provocative  injection  later,  and  vice  versa. 

In  actual  practice  we  know  that,  provided  the  patient  has  been  well  treated 
— and  I  am  now  thinking  of  those  who  never  had  salvarsan — and  that,  provided 
four  or  five  years  have  elapsed  before  marriage,  the  percentage  of  those  who 
infect  their  wives  is  so  ridiculously  small,  that,  when  a  patient  comes  for  advice 
upon  this  point,  one  almost  feels  inclined  to  tell  him  that  there  is  no  risk.  Then 
the  cases  in  which  infection  has  been  conveyed  pass  through  one's  mind,  and  as 
such  instances  are  often  such  sad  ones,  it  requires  many  hundreds  of  successful 
cases  to  set  off  against  one  unsuccessful  one. 

I  will  now  mention  two  cases.  In  one  the  husband  had  no  salvarsan  before 
marriage,  and  in  the  other  he  had. 

Case  78. — ^The  patient  contracted  syphihs  five  years  before  he  married,  and  for 
the  first  three  of  those  }'ears,  he  was  treated  with  mercury.  He  had  never  developed 
a  recurrence,  and,  wlien  his  wife  became  infected,  his  Wassermann  reaction  was 
negative.     They  had  been  married  for  twelve  years,  and,  with  the  exception  of  the 


488  EUGENIC    ASPECT   OF    VENEREAL   DISEASE. 

occasion  upon  which  the  infection  was  conveyed,  the  luisband  had  always  worn 
a  preventative.  The  wife  developed  very  severe  syphilis.  Within  a  few  weelcs 
of  the  appearance  of  the  rash,  she  developed  a  unilateral  optic  neuritis.  She 
quickly  became  blind  in  the  affected  eye,  in  spite  of  treatment,  and  ultimately  the 
blind  eye  had  to  be  removed. 

Case  79. — The  husband  contracted  syphilis  in  1906.  He  was  treated  with 
mercury  for  three  years,  and  took  mercurj^  again  for  one  year  before  he  married, 
and  as  an  extra  precaution  he  had  three  injections  of  salvarsan.  There  had  never 
been  a  recurrence.  The  patient  married  in  June,  1912,  and  in  October,  1913,  he 
brought  his  wife  to  see  me,  and  she  had  well  marked  generalised  syphilis. 

I  could  cite  other  cases,  but  these  two  will  suffice  to  show  how  difficult  it  is 
to  advise  a  patient,  and  what  a  slender  reed  to  lean  upon  is  the  time  limit.  Every 
case  should  be  considered  individually,  and,  when  I  am  consulted  upon  this  point, 
I  first  of  all  find  out  whether  the  treatment  has  been  adequate  or  inadequate.  I 
then  attempt  to  gain  as  much  knowledge  of  the  "  man  "  as  I  can.  and,  finally,  I 
try  to  ascertain  the  kind  of  sore  which  the  patient  had,  and  the  amount  of  resistance 
he  brought  up  to  combat  the  infection. 

The  question  of  treatment  we  have  already  considered,  and  we  have  now  the 
"  man"  himself  to  discuss.  If  the  patient  is  an  intelligent  man,  and  if  there  is  reason 
to  think  that  he  will  be  able  to  follow  the  line  of  argument  which  is  passing  through 
one's  own  brain,  the  whole  matter  should  be  laid  before  him,  and  he  should  be 
left  to  choose  whether  he  will  run  the  infinitesimal  risk  or  not. 

If  the  patient  is  nervous,  and  if  there  is  reason  to  think  that  his  future  life  would 
be  rendered  miserable  by  being  told  that  a  risk  existed,  provided  other  things  are 
equal,  it  is  best  to  take  the  risk  upon  one's  own  shoulders,  and  to  tell  him  that  he 
may  marry  without  entertaining  any  qualms. 

Since  we  do  not  at  present  discriminate  between  our  cases  of  syphilis,  but  regard 
all  cases  as  being  alike,  and  prescribe  the  same  treatment  for  all,  we  always  must  be 
indefinite  when  we  are  requested  to  advise  on  the  matter  of  marriage.  I  have  no 
doubt  in  my  own  mind,  that  cases  of  syphilis  vary  enormously,  and  that  a  relationship 
exists  between  the  kind  of  sore,  the  degree  of  the  enlargement  of  the  lymphatic 
glands,  and  the  future  course  of  the  disease,  hence,  indirectly,  its  degree  of 
infectivity. 

I  am  unable  at  present  to  lay  down  any  hard  and  fast  rules,  since  the  matter 
can  only  be  solved  by  chnical  methods,  and  these  have  not  yet  been  sufficiently 
long  in  force. 

The  plan  is  to  note  very  carefully  the  kind  of  sore  which  the  patient  has,  the 
phases  of  the  Leucoctjtozoon  sypJiiUdis  which  it  reveals  in  section,  and  the  degree 


MARRIAGE.  489 

of  the  enlargement  of  tlie  lymijhatic  glands.     Then  to  watch  the  career  of  the 
patient,  and  to  note  what  happens  when  he  marries. 

Although  I  can  only  speak  in  general  terms  at  present,  I  can  say  that  the  risks 
of  a  man  infecting  his  wife  are  greater  when  the  sore  is  of  the  papulo-indurative- 
erosive  type  than  when  the  sore  is  of  the  papulo-uou-indurative-ulcerative  type. 
The  prognosis  is  distinctly  better  in  those  cases  in  which  the  lymphatic  glands  are 
markedly  enlarged,  than  in  those  in  which  they  are  scarcely  enlarged,  but  are 
abnormally  hard.  It  must  be  remembered  that,  in  the  papulo-ulcerative  chancre, 
the  lymphatic  glands  may  remain  unaltered,  and  that  in  many  of  the  cases  in  which 
they  become  enlarged,  the  enlargement  is  due  to  a  secondary  infection. 

If  a  man  has  had  a  recurrence,  it  does  not  follow  that  the  risks  of  his  marrying 
are  any  greater  than  those  of  a  man  who  has  had  no  recurrence,  since  the  fact  that 
a  man  gets  an  orbicular  syphilide  of  his  arm,  does  not  mean  that  he  is  any  more 
likely  to  have  dormant  spores  in  his  sexual  organs  than  a  man  who  has  never  had 
a  recurrence.  In  actual  practice,  we  think  that  a  man  who  has  had  a  recurrence 
runs  greater  risks.  As  our  knowledge  is  so  incomplete  at  present,  it  is  as  well  to 
think  that  this  is  true,  as  it  is  well  to  err  on  the  side  of  caution. 

Another  factor  which  has  to  be  taken  into  account,  is  the  part  of  the  body 
which  has  been  attacked  by  the  syphilis.  This  aspect  of  the  question  has  nothing 
to  do  with  the  risk  of  infection,  but  only  concerns  the  future  of  the  man  and  wife. 

If  the  patient  has  a  high  blood  pressure,  caused  by  the  syphilis,  and  ther 
is  any  reason  to  fear  that  an  arterial  lesion  is  likely  to  cut  short  his  life,  new  points 
are  presented,  and   they   require  very   careful   consideration,  before   marriage   is 
advised  or  not. 

Again,  if  the  patient  has  a  lesion  of  his  central  nervous  system,  and  it  is  feared 
that  he  may  later  develop  a  degenerative  lesion,  the  doctor  must  carefully  consider 
whether  a  few  years  of  conjugal  happiness  are  compensated  by  the,  maybe,  many 
years  of  chronic  invalidism  of  the  husband. 

For  some  reason  or  other,  recent  authorities  have  imagined  that  there  is  a 
special  breed  of  spirochaeta  which  will  give  rise  to  nervous  lesions,  and  another 
breed  which  will  give  rise  to  systemic  lesions,  and  so  on. 

Hence,  if  a  man  who  develops  a  degenerative  nervous  lesion  infects  his  wife 
or  his  children,  it  is  assumed  that  the  wife  or  the  children  are  more  likely  to  develop 
nervous  syphilis  than  systemic  svphilis. 

I  mention  this,  because,  if  such  a  view  were  true,  the  advice  one  would  give 
to  a  patient  who  one  feared  might  develop  a  degenerative  nervous  lesion,  would  , 
on  this  score  alone,  be  certainly  not  to  marry. 

I  have  had  the  opportunity  of  seeing  and  examining  many  families  in  which 


490  EUGENIC    ASPECT   OF   VENEREAL   DISEASE. 

the  husband  had  a  degenerative  nervous  lesion.  I  have  notes  of  five,  in  which 
the  wife,  or  the  wife  and  children,  were  syphilitic  ;  but  I  have  never  seen  a  case 
in  which  the  wife  or  children  had  a  nervous  lesion.  Cases  have  been  reported  in 
books,  and  the  same  cases  have  been  copied  from  one  book  into  another,  so  that, 
at  first  sight,  a  reader  might  imagine  that  these  commonly  occurred.  I  feel  certain 
that  they  are  only  coincidences,  because  all  experimental  work  completely 
negatives  the  idea  that  there  are  special  breeds  of  organisms  that,  on  the  one  hand, 
produce  nervous  syphilis,  and,  on  the  other  hand,  systemic  syphilis. 

If  a  woman  has  had  svphilis,  and  has  been  well  treated,  the  chances  of  her 
infecting  her  husband  are  nil ;  but,  however  drastic  the  treatment  has  been,  there 
is  always  a  risk  that  her  children  will  be  syphilitic.  Therefore,  as  has  been  already 
stated,  once  a  woman  has  had  syphilis,  in  spite  of  the  treatment  she  has  already 
had,  she  must  be  treated  throughout  the  whole  period  of  each  succeeding  pregnancy. 

Gonorrhoea. 

Although  gonorrhoea  is  a  less  serious  disease  than  syphilis,  when  it  becomes 
chronic  it  is  certainly  more  difficult  by  treatment  to  render  the  patient  non- 
infectious. The  man  and  the  woman  will  be  considered  separately,  but,  before 
going  deeply  into  the  subject,  I  would  like  to  give  the  warning  that  a  negative 
bacteriological  diagnosis  has  absolutely  no  significance  whatsoever.  When  the 
question  of  infectivity  is  concerned,  it  is  a  waste  of  time  and  money  to  examine 
bacteriologically  the  urethral  and  prostatic  secretions  of  the  man  and  the  cervical 
secretion  of  the  woman.  The  advice  to  be  given  in  the  case  of  gonorrhoea,  as  in 
syphilis,  depends  mainly  upon  clinical  experience. 

When  a  man  seeks  advice  on  the  question  of  marriage,  the  first  point  to  be 
ascertained  is  as  to  whether  he  has  ever  had  a  recurrence  or  a  metastatic  lesion. 
If  not,  the  prospects  are  good  from  the  start,  while  if  he  has  had  a  recurrence  or 
a  metastatic  lesion,  the  risks  of  his  infecting  his  wife  are  infinitely  greater. 

We  will  first  of  all  consider  the  patient  who  has  never  had  a  recurrence  or  a 
metastatic  lesion. 

From  such  a  patient,  it  is  important  to  ascertain  when  he  became  infected, 
the  period  that  has  elapsed  since  he  last  had  any  signs  of  a  discharge,  and  whether 
the  infection  reached  the  posterior  part  of  his  urethra  and  prostate,  or  not.  He 
should  then  be  asked  whether  sexual  connection,  nocturnal  emissions,  and  alcohol 
have  any  effect  upon  the  condition.  If  not,  the  chances  are  that  he  is  cured,  while 
if  the  status  quo  is  not  maintained,  the  chances  are  that  he  is  not  cured,  and  there- 
fore is  infectious. 


MARRIAGE.  491 

The  urethra  and  prostate  should  then  be  very  carefully  examined,  and  great 
attention  should  be  paid  to  the  dilatability  of  the  urethra ;  this  can  be  gauged 
by  Kollmann's  anterior  and  posterior  dilators.  If  the  dilatability  is  below  the 
normal,  the  chances  are  that  there  are  gonococci  hidden  in  the  follicles  or  in  the 
subepithelial  tissue.  Dilatation  will  probably  wake  them  up,  and  a  big  injection 
of  a  potent  non-sensitised  vaccine  will  also  help  to  do  this.  If  the  dilatability 
is  normal,  and  if  a  vaccine  does  not  alter  the  statua  quo,  the  patient  can  be  passed 
as  a  fit  candidate  for  marriage. 

If  the  patient  has  had  a  recurrence  or  a  metastatic  lesion,  the  same  tests 
should  be  applied,  but  the  additional  factor  of  a  secondary  infection  comes  in.  In 
other  words,  the  tests  employed  above  are  not  quite  so  conclusive,  in  a  recurrent 
case.  A  peculiarity  of  some  of  these  cases  is,  that  an  occasional  sexual  connection 
may  not  alter  the  status  quo,  but,  when  marital  connection  is  indulged  in,  it  may 
set  up  a  copious  discharge,  which  wall,  in  its  turn,  be  certain  to  infect  the  wife. 
Occasionally  the  discharge  may  not  be  copious  ;  indeed,  it  may  not  even  be 
increased,  and  yet  the  wife  becomes  infected.  The  infection  runs  its  usual  course 
— that  is,  it  is  first  acute,  then  subacute,  and  finally  chronic,  or  the  wife's 
infection  may  be — to  use  an  Irishism — chronic  from  the  start.  It  is  odd  how 
frequently  gonococcal  lesions  are  chronic  from  the  start,  and  yet  the  point  appears 
never  to  have  received  any  recognition.  I  have  seen  cases  of  gonococcal  epididy- 
mitis, in  which  the  whole  of  the  caput  minor  has  become  stone-like,  without  the 
patient's  ever  being  aware  that  he  had  had  an  infection  there.  I  mention  the 
epididymis,  because  it  occurs  in  such  a  tender  organ  that  an  acute  or  a  subacute 
infection  of  it  could  scarcely  be  overlooked.  An  analogy  exists  between  a  man 
who  has  entered  the  generahsation  stage  of  syphilis  and  the  man  who  has  a  recurrent 
urethritis  or  a  metastatic  gonococcal  lesion.  That  is  to  say,  in  both  cases  one  may 
make  a  mistake  in  advising  a  patient  to  marry. 

All  the  tests  just  mentioned  should  be  tried,  and,  if  the  patient  is  an  intelligent 
man,  the  position  should  be  discussed  openly  with  him  ;  if  not,  then  the  doctor 
must  run  the  risk  of  making  a  mistake,  and  being  blamed  afterwards  by  the  patient 
for  it. 

Speaking  generally,  it  is  not  difficult  to  tell  when  a  man  is  cured.  In  the  case 
of  a  woman,  it  is  well  nigh  impossible. 

In  a  woman  there  may  be  gonococci  hidden  in  Bartholin's  glands  or  in  the  cervix, 
for  years.  They  may  be  the  source  of  infection,  without  necessarily  producing 
any  signs  or  symptoms  in  the  person  who  harbours  them.  The  provocative  vaccine 
test  is  difficult  to  interpret  in  a  woman,  and  even  if  Bartholin's  glands  and  the  cervix 
are  harbouring  gonococci  in  a  chronic  infection,  a  bacteriological  examination  will, 


492  EUGENIC   ASPECT   OF    VENEREAL   DISEASE. 

in  iiine  cases  out  of  ten,  fail  to  reveal  them.  If  the  patient  has  never  had  sexual 
connection,  the  chances  are  that  the  cervix  has  never  been  infected.  In  such  a 
case,  provided  the  treatment  has  been  good,  marriage  may  be  advised.  In  a 
patient  who  has  had  sexual  connection,  the  chances  are  that  she  has  had  a  cervicitis. 
The  long  presence  of  gonococci  in  the  cervix  leads  to  fibrous  tissue  formation,  and 
destroys  the  dilatability,  as  is  the  case  with  the  urethra.  If  the  dilatability  of  the 
cervix  is  destroyed,  the  patient  will  almost  certainly  suffer  from  dysmennorrhoea, 
hence  some  information  may  be  gained  by  going  into  this  question.  If  the  patient 
suffers  from  mennorrhagia  or  metrorrhagia,  the  chances  are  that  she  still  has  an 
active  gonococcal  infection. 

It  is  extremely  seldom  that  the  true  position  of  affairs  can  be  pointed  out  to  a 
woman,  therefore,  in  advising  women  re  marriage,  we  must  all  expect  to  make 
mistakes. 

1  Hutchinson   (1899   and   1902),    Internat.   Congress   for    the    Proph_ylaxis   of    Venereal 

Diseases.     Brussel.s. 

2  Fournier  (1890),  "  Syphilis  et  Mariage."     Paris. 

3  Gougerot  (1914),  "Le  Traitement  d.  1.  Syph.  en  Clientele."     A.  Maloine.     Paris. 


CHAPTER  XLIV. 
VENEREAL  DISEASE  AND  PUBLIC  HEALTH. 

Venereal  diseases  cannot  as  yet  be  regarded  as  having  come  within  the  scope 
of  preventive  medicine.  The  advances  made  during  the  present  century  have 
tended  rather  to  the  improvement  in  diagnosis  and  treatment,  than  to  the  pre- 
vention of  the  spread  of  infection. 

The  importance  of  these  additions  to  the  sum  of  our  knowledge  is,  however, 
apparent,  if  it  be  reaUsed  that  the  disease  nuist  be  diagnosed  before  the  spread  of 
infection  can  be  prevented.  On  the  other  hand,  there  is  an  unfortunate  tendency 
at  the  present  time  to  rely  upon  the  aid  of  bacteriology  and  pathology  for  diagnosis, 
rather  than  upon  cHnical  evidence. 

The  various  tests  which  have  been  discovered  and  taught  render  the  medical 
practitioner  more  dependent  upon  the  work  of  a  laboratory  than  upon  his  own 
knowledge  of  the  cHnical  aspect  of  the  disease.  Many  of  these  tests  do  not  prove 
to  be  so  accurate  as  they  were  beheved  to  be,  when  they  were  first  of  all  discovered  ; 
cUnical  knowledge  of  disease  must  always  remain  the  most  reliable  basis  for  work. 
This  is,  perhaps,  especially  the  case  in  regard  to  syphihs,  when  the  trained  eye  can 
frequently  enable  a  decision  to  be  made  some  considerable  period  before  the 
diagnostic  tests  are  appHcable.  Broadly  speaking,  a  case  of  syphiUs  is  not  diagnosed 
to-day  at  a  much  earlier  period  of  the  disease  than  was  done  many  years  ago. 
This  regrettable  fact  is  largely  owing  to  the  absence  of  chnical  tuition  in  the  diagnosis 
of  the  disease,  in  the  medical  schools  of  this  country. 

Earlier  and  more  accurate  diagnosis  of  the  disease  is  essential,  if  the  period 
of  infection  is  to  be  shortened,  and  such  diagnosis  must  be  made  upon  clinical 
evidence.  We  do  not  as  yet  know  whether  the  incidence  of  venereal  disease  is 
increasing  or  decreasing.  It  is  hkely,  however,  that,  were  the  full  extent  of  this 
social  evil  disclosed,  the  pubHc  would  be  awakened  somewhat  rudely  to  the  dangers 
by  which  they  are  surrounded,  as  regards  the  possibility  of  infection  by  venereal 
disease. 

Considerable  attention   has  recently   been  paid  to  the  relation  of  venereal 


494  EUGENIC   ASPECT   OF   VENEREAL   DISEASE. 

diseases  to  public  health,  and  a  part  of  the  subject,  upon  which  there  has  been 
much  criticism,  is  notification.  Before  notification  could  be  advised,  very  careful 
attention  would  have  to  be  paid  to  the  effects  it  has  had  in  the  case  of  those  diseases 
which  have  been  notifiable  for  some  time  past.  It  is  only  natural  that  the  advocates 
for  notification,  say  of  scarlet  fever,  for  instance,  should  be  able  to  produce  statistics, 
to  the  effect  that  notification  has  resulted  in  a  diminished  incidence  of  the  disease. 
All  statistics  are  apt  to  be  fallacious,  and  perhaps  none  more  so  than  medical  statistics, 
for  the  simple  reason  that  it  requires  very  expert  knowledge  to  draw  up  accurate 
figures,  and,  in  compiling  medical  statistics,  there  are  more  paths  open  for  the 
entrance  of  error  than  in  the  other  sciences.  There  are  many  people  who  do  not 
beheve  that  notification  has  had  any  appreciable  result  in  lessening  such  a  disease 
as  scarlet  fever.  In  the  case  of  most  of  the  notifiable  diseases,  the  most  infectious 
and  contagious  period  has  been  passed,  before  the  case  is  diagnosed,  and  therefore 
can  be  notified.  If  syphihs  were  made  a  notifiable  disease,  the  difficulty  just  raised 
would  have  to  be  most  carefully  considered.  Furthermore,  there  are  many  objections 
to  notification.  In  the  first  place,  there  is  no  a  priori  reason  for  assuming  that  there 
would  be  less  syphilis,  if  it  were  made  a  notifiable  disease.  In  the  second  place, 
men  would  not  be  prepared — even  if  they  knew — to  state  their  source  of  infection, 
and  women  would  in  many  cases  not  know  from  whom  they  had  contracted  the 
disease.  For  notification  to  be  as  successful  as  possible,  it  would  be  necessary, 
in  every  case,  to  trace  the  source  of  infection.  When  preventive  measures  are 
under  consideration,  the  greatest  difficulty  arises  from  the  woman's  side,  owing 
to  the  fact  that  many  women  are  entirely  ignorant  of  the  presence  of  a  sore,  and 
all  women  who  contract  syphilis  are  infectious  for  a  long  period,  without  being 
aware  of  the  fact. 

I  think  it  may  safely  be  said,  that  notification  of  syphiUs  would  be  devoid  of 
any  success. 

The  next  point  to  be  considered  is  the  registration  of  prostitutes.  The 
registration  of  prostitutes,  and  the  sanctioning  of  Ucensed  houses  has  had  a  trial 
of  many  years'  duration  on  the  Continent,  with  httle  or  no  success.  The  main 
reason  for  the  failure  is  the  enormous  increase  in  clandestine  prostitution  which 
notification  has  produced.  The  time  is  probably  not  very  far  distant,  when  we 
shall  see  these  measures  abohshed.  On  the  face  of  it,  it  seems  grossly  unfair  that 
women  should  be  punished  when  they  contract  a  venereal  disease,  and  that  men 
should  be  allowed  to  go  scot  free.  For  a  law  to  be  of  any  use,  it  must  be  just,  and, 
in  this  case,  it  nnist  apply  equally  to  both  sexes.  One  thing,  I  think,  is  certain, 
and  that  is,  that  prostitution  can  never  be  abohshed  ;  another  thing,  equally  certain, 
is,  that  men  are  never  going  to  be  dissuaded  from  ha\'ing  sexual  connection.     Both 


PUBLIC   HEALTH.  495 

may  be  lessened,  perhaps,  but  never  \\ill  they  be  exterminated  ;  therefore,  whatever 
may  be  done  in  the  future,  with  the  idea  of  diminishing  venereal  disease,  must  be 
undertaken,  with  a  full  recognition  of  these  facts.  Several  attempts  have  been 
made  to  -  engage  public  opinion  upon  this  subject,  and  recently  two  committees 
have  been  formed  in  this  country,  to  inquire  into  the  means  which  might  diminish 
the  incidence  of  syphihs. 

One  committee  has  been  formed  at  the  instigation  of  the  Eugenic  Society, 
and  the  other  constitutes  the  Royal  Commission. 

The  aims  of  the  former  appear  to  be,  to  lessen  syphilis  by  minimising  the  risks 
which  people  run.  As  an  indirect  method,  probably  none  better  exists.  The 
public  are  to  be  warned  of  the  risks  they  run,  when  they  indulge  in  extra-matri- 
monial intercourse.  Lectures  are  to  be  given  to  young  adults,  and  it  is  hoped  not 
onty  that  Universities  and  Schools  will  assist  in  the  matter,  but  also  that  all  mothers 
and  fathers  will  take  their  children  into  theu'  confidence,  pointing  out  to  them 
the  enormous  dangers  they  run,  the  sequelae  that  may  follow,  and,  above  all,  that 
they  will  withhold  any  threat  in  case  a  misfortune  should  occur. 

One  of  the  greatest  difficulties  we  have  now  to  contend  with,  is  the  attitude 
which  many  sons  assume  will  be  adopted  towards  them  by  their  fathers,  should 
the  fathers  learn  that  they  have  contracted  a  venereal  disease.  This  often  results 
in  a  man  coming  up  for  advice,  when  it  is  too  late. 

Most  fathers  have  themselves  run  the  risk  in  their  youths,  but  it  is  a  peculiarity 
of  the  British  mind  that  it  regards  extra-matrimonial  intercom-se  as  a  sin,  only 
when  a  venereal  disease  results  from  it. 

The  Eugenic  Committee  have  very  wisely  made  up  their  minds  to  refrain  from  the 
mention,  in  their  lectures,  of  all  Malthusian  apphances.  Holding  out  preventatives 
before  the  hearers  would  naturally  defeat  their  purpose.  Malthusian  apphances  are 
by  no  means  always  such  a  safeguard  as  they  are  supposed  to  be.  For  instance,  I  have 
frequently  seen  a  chancre  on  the  pubis  or  scrotum  in  patients,  who  habitually  wore 
condoms,  and  the  only  two  patients  I  have  come  across,  whose  custom  it  was  to  use 
Metschnikoff's  ointment  (calomel),  both  contracted  syphihs. 

There  is  no  doubt  that  the  anti-alcohol  crusade  has  exerted,  and  will  still  more, 
in  the  future,  exert  a  beneficial  action,  since  a  very  large  percentage  of  cases 
of  venereal  disease  are  contracted,  while  the  patient  is  under  the  influence  of 
alcohol. 

The  greatest  proof  we  have  that  these  indirect  measures  are  productive  of 
good  is  seen  in  the  diminution  of  venereal  disease  in  the  Navy  and  Ai-my,  during 
recent  years.  ) 

This  decrease  of  venereal  disease  in  the  Services  can  in  no  way  be  caused  by 


496  EUGENIC   ASPECT    OF   VENEREAL   DISEASE. 

our  better  methods  of  treatment,  since  the  source  of  the  infection — the  women- 
is  not  considered. 

The  decrease  is  due  to  the  greater  abstinence  from  alcohol,  to  an  improvement 
in  the  moral  tone  of  the  men,  to  the  greater  attention  that  is  paid  to  outdoor 
exercises,  and  to  the  less  wide  social  gulf  between  the  officers  and  their  men. 

The  aim  of  the  Eoyal  Commission  appeared  to  be,  to  collect  statistics  of  the 
incidence  of  syphilis,  with  the  idea  of  seeing  whether  the  disease  was  on  the  increase 
or  decrease ;  of  the  role  syphilis  plays  in  the  causation  of  other  diseases  ;  of  the 
number  of  deaths  attributable  to  this  disease ;   and  of  the  results  of  treatment. 

The  report  has  not  been  issued  yet,  but,  from  the  evidence  already  given,  it 
would  appear  that,  so  far  as  obtaining  these  statistics  is  concerned,  the  Commission 
has,  unfortunately,  not  been  very  successful. 

It  is  the  general  impression,  that  the  great  strides  which  treatment  has  made, 
in  the  last  few  years,  are  going  very  materially  to  diminish  the  amount  of  syphilis, 
even  if  they  do  not  abohsh  it.  Supposing  that  we  could  get  every  patient  under 
treatment  the  moment  that  he  or  she  was  conscious  of  infection  with  syphilis,  it 
would  certainly  diminish  syphilis,  but  it  is  doubtful  whether  the  decrease  would 
be  very  appreciable,  smce,  after  all,  it  is  only  shutting  the  stable  door  after  the 
horse  is  gone.  No  disease  has  ever  yet  been  stamped  out  by  treating  it,  nor  is  it 
ever  likely  that  such  will  be  the  case. 

In  the  first  place,  patients  cannot  be  put  under  treatment  the  moment  the 
initial  lesion  appears — for  two  main  reasons  :  (1)  because  of  the  lack  of  clinical 
knowledge  of  those  who  are  called  upon  to  diagnose  the  early  syphilitic  lesions ; 
(2)  because  many  women  contract  syphilis  without  knowing  it  until  the  rash 
appears. 

In  the  second  place,  it  must  not  be  .forgotten  that,  however  good  may  be 
statistics  dealing  with  the  results  of  treatment,  such  statistics  will  only  hold  good 
for  the  time  being,  for  syphilologists  are  by  no  means  agreed  upon  the  best  method 
of  treatment,  and  none  of  us  yet  knows  how  all  the  cases  treated  by  these  up-to-date 
methods  will  fare  in  the  future. 

Added  to  this,  is  the  fact  that  all  the  statistics  deaUng  with  treatment  have 
been  based  not  upon  clinical  experience  but  upon  laboratory  methods,  which  have 
since  been  shown  to  be  less  accurate  than  was  at  first  beUeved. 

Apart  from  the  idea  that  treatment  is  seriously  going  to  diminish  syphilis, 
which  I  do  not  for  one  moment  think,  we  have  to  consider  the  patient  who  is 
infected. 

Every  one  is  now  agreed  that,  for  a  cure  of  syphilis  to  be  guaranteed,  the 
patient  must  be  put  under  treatment  before  he  enters  the  generalisation  stage. 


PtJBLIC   HEALTH.  -197 

This  necessitates  two  things :  (1)  that  the  patient  seeks  advice  the  moment  he 
notices  a  sore  ;   (2)  that  the  medical  man  knows  what  the  sore  is,  when  he  sees  it. 

Point  number  one  will  be  achieved  partly  by  the  wide  dissemination  of  proper 
knowledge  upon  the  subject,  and  this  is  part  of  the  programme  of  the  Eugenic 
Society ;  partly  by  the  Government  stepping  in  and  making  quackery  illegal, 
and  preventing  druggists  from  either  givmg  advice  or  seOing  remedies  for  this 
complaint,  without  a  prescription  signed  by  a  medical  man,  and  partly  by  every- 
body realising  that  syphilis  is  a  disease,  and  not  a  punishment  for  immorality. 
Point  number  two  will  be  achieved,  when  every  medical  student  of  the  present  and 
future  is  given  clinical  tuition  in  venereal  diseases. 

The  London  Lock  Hospital  has  the  finest  cHnical  material  in  the  world,  yet, 
from  the  point  of  view  of  tuition,  this  splendid  material  is  all  wasted. 

Men  prefer  to  learn  all  about  the  SpirocJiaeia  pallida  and  the  Wassermann 
reaction,  mainly  because  laboratory  knowledge  is  easier  to  acquire  than  is  clinical 
knowledge,  but  it  is  also  very  largely  due  to  the  fact  that  there  are  not  enough  men, 
whose  knowledge  of  venereal  diseases  is  sufficient  to  warrant  them  in  undertaking 
tuition  in  this  subject.  An  early  diagnosis  needs  clinical  experience,  not  expert 
bacteriological  knowledge  as  to  how  to  look  for  spirochaetae,  and  how  to  be  able 
to  recognise  the  Spirochaeta  pallida  when  seen.  The  hasty  search  for  an  organism, 
which  is  sometimes  not  present,  and  for  the  application  of  an  empirical  pathological 
test,  is  hindering  advance  considerably.  Let  us  see  for  a  moment  what  effect  it 
has  had  upon  the  evidence  which  the  Royal  Commission  has  so  far  obtained. 

Summing  up  the  evidence,  it  can  be  arranged  thus : — 

(a)  An  examination  of  all  sores  for  the  Spirochaeta  pallida  should  become 
more  general. 

(b)  The  Wassermann  reaction  should  be  carried  out  more  generally  than  is 
now  the  case. 

(c)  There  should  be  a  widespread  distribution  of  public  laboratories,  in  which 
these  tests  could  be  carried  out  gratuitously. 

{d)  All  special  hospitals  for  venereal  diseases  should  be  abohshed. 

I  need  not  dilate  upon  the  futihty  of  putting  the  first  tw^o  points  into  practice, 
as  the  reader  will  have  seen  the  reason  by  now,  if  he  has  read  the  earher  chapters 
of  this  book. 

As  regards  the  other  points.  Better  chnical  training  would  render  public 
laboratories  superfluous  ;  but  let  lis  look  at  the  suggestion  from  other  points  of 
view. 

It  is  proposed  to  do  away  with  special  hospitals,  because  the  patients  do  not 
like  attending  them,  and  hence  many  are  kept  away  from  treatment.     Most  of  the 

2i2 


498  EUGENIC   ASPECT    OF   VENEREAL    DISEASE. 

witnesses  who  were  of  this  mind  had  never  been  in  a  special  hospital  for  venereal 
diseases.  Let  us  take  the  London  Lock  Hospital,  and  see  what  the  true  state  of 
affairs  is.  The  numbers  attending  are  steadily  increasing.  Several  hundreds  of 
the  patients  were  asked  if  they  minded  coming  to  the  Lock  Hospital.  None 
appeared  to  have  any  objection.  Asked,  further,  why  they  attended,  they  were 
unanimous  in  saying,  that  it  was  because  they  received  better  treatment  there 
than  elsewhere.  The  main  object  of  the  average  hospital  patient  is  to  get  well, 
and  he  will  go  where  the  treatment  is  best.  He  would  not  mind,  if  the  hospital 
was  called  "  Hell." 

If  special  hospitals  are  so  undesirable,  why  put  up  special  laboratories  ?  It 
is  simply  jumping  from  the  frying-pan  into  the  fire.  Supposing,  on  the  other  hand, 
special  laboratories  were  erected,  what  criterion  have  the  authorities  got,  that 
they  are  going  to  get  able  men  to  work  them,  or  patients  to  attend  them  ?  PubUc 
laboratories  are  not  going  to  make  the  average  hospital  patient  seek  the  advice  of 
a  general  practitioner  any  sooner  than  he  does  now,  and  it  will  have  to  be  through 
a  general  practitioner  that  he  finds  his  way  to  a  laboratory.  Assuming,  for  the 
sake  of  argument,  that  it  did  so,  the  practitioner's  acumen  for  interpreting  a 
pathological  report  would  probably  not  be  of  the  best ;  hence,  the  pathologist 
would  have  to  be  a  clinician  as  well,  without  the  latter's  knowledge  or  experience. 

To  Sum  Up. 

Treatment  is  going  to  diminish  syphilis,  but  a  diminished  consumption  of 
alcohol  is  going  to  do  more  towards  this  end,  and  a  raising  of  the  standard  of  public 
morahty  is  going  to  do  most.  Unfortunately,  however  great  the  influence  of  all 
three  will  be,  it  will  not  mean  the  abohtion  of  syphihs.  If  syphihs  is  to  be  stamped 
out,  a  means  of  preventing  it  will  have  to  be  found ;  hence,  one  thing  that  the 
Commission  might  do  would  be  to  impress  upon  the  Government  the  importance 
of  prevention.  First-rate  workers  might  be  obtained  to  tackle  the  subject,  and 
there  is  no  reason  why  as  much  success  should  not  be  achieved  in  syphilis,  as  Jenner 
achieved  in  smallpox.  In  the  meantime,  the  pubhc  should  be  warned  of  the 
seriousness  of  syphihs,  and  of  the  necessity  for  instant  medical  advice.  The  present 
and  the  future  generations  of  medical  men  could,  with  advantage,  be  taught  the 
clinical  side  of  syphihs,  the  London  Lock  Hospital  should  be  much  more  freely 
used  for  this  purpose  than  is  now  the  case,  and  it  occurs  to  me  that  instead  of 
having  pubhc  laboratories,  it  would  be  more  to  the  point  to  have,  in  every  town 
of  a  certain  size,  one  or  more  experts,  according  to  the  size,  to  whom  a  case  could 
be  referred  immediately  for  a  chnical  diagnosis. 


Part    II. 

THE    BIOLOGY    OF    INFLAMMATION,    AND    ITS 
RELATIONSHIP  TO  MALIGNANT  DISEASE. 

INTRODUCTIOiV. 

No  book  on  Sjrphilis  would  be  considered  complete,  unless  it  contained  a  chapter 
on  the  histology  of  the  vario\is  lesions.  Looking  at  a  skin  section  under  the 
microscope,  and  given  no  clue  as  to  the  clinical  aspect  of  the  case,  it  is  almost 
impossible  to  make  a  correct  diagnosis  of  the  disease,  unless,  of  course,  the  picture 
has  marked  characteristics  as,  for  instance,  are  to  be  seen  in  Molluscum  conlagiosum 
Syphilitic  lesions  are  granulomata  ;  that  is  to  sa\%  the  cellular  infiltration  is  made 
up  chiefly  of  lymphocytes  and  plasma  cells.  There  may  be  some  giant  cells,  and 
the  vessels  usually  exhibit  varying  degrees  of  arteritis  and  endarteritis.  Almost 
all  chronic  inflammatory  lesions  become  granulomata,  and  any  granuloma  may 
present  the  above  features  in  diverse  degrees  of  sharpness  or  intensity.  Although 
an  arteritis  and  endarteritis  are  more  marked  in  a  syphilitic  granuloma  than  in 
any  other,  owing  to  the  fact  that  the  organism  has  a  predilection  for  developing 
in  the  walls  of  vessels,  these  changes  may  be  absent  in  the  section  under  examination, 
and  they  may  be  found  in  a  tuberculous  granuloma,  for  instance. 

Hence,  broadly  speaking,  unless  the  observer  has  the  clinical  knowledge  of 
the  case,  it  is  impossible  to  distinguish  a  syphilitic  from  any  other  granuloma. 
Fortunately,  the  phases  of  the  Leucocytozoon  syphilidis  can  be  so  easily  demonstrated 
in  the  sections,  that  there  is  no  difficidty  now  in  making  a  diagnosis  from  a  histological 
specimen,  provided  it  has  been  stained  according  to  the  details  given  in  Chapter  VI. 
When  the  asexual  stage  only  develops,  it  may  be  practically  impossible  to  dis- 
tinguish between  a  section  from  a  case  of  syphilitic  coccidiosis,  and  a  section  from 
a  case  of  the  other  forms  of  coccidiosis  which  I  have  described. ^^  When  one  considers 
that  the  host  protects  itself  against  an  infection  by  an  increased  formation  of  its 
leucocytes,   and  that  the  leucocyte  relied   upon   in   all   chronic   infections   is  the 


500  BIOLOGY    OF   INFLAMMATION   AND    MALIGNANT   DISEASE. 

lymphocyte,  one  would  not  reasonably  expect  to  find  histological  differences  in 
the  granulomata  of  varied  origin. 

The  difference  in  the  nature  of  the  host's  response  against  syphilis,  tubercle, 
&c.,  which  in  each  case  is  specific,  does  not  lie  in  an  altered  form  of  lymphocyte 
or  plasma  cell,  but  in  the  stereo-chemical  molecular  configuration  of  the  lipoid- 
globulin  in  the  protoplasm  of  these  cells. 

Our  present  knowledge  only  enables  us  to  tell,  by  micro-chemical  and  micro- 
physical  tests,  that  the  protective  substance  in  all  chronic  inflammatory  diseases 
is  a  lipoid-globulin.  We  have  yet  to  discover  tests  which  -ttill  differentiate  the 
various  specific  stereo-chemical  properties  of  these  lipoid-globulins.  Since  we 
cannot  diagnose,  by  pure  histology,  a  syphilitic  from  any  other  granuloma,  I  have 
thought  it  wiser  to  describe  the  changes  which  the  epithelial  cells,  lymphocytes,  and 
other  cells  undergo  in  any  chronic  inflammation.  A  description  of  this  kind  will 
cover  a  wider  field  than  could  otherwise  have  been  the  case,  it  will  throw  light  upon 
various  points  which  have  hitherto  remained  enigmas,  and  I  trust  it  will  make 
a  very  large  chapter  in  histology  much  simpler,  and  at  the  same  time  more  interesting. 
To  attain  this  end,  I  will  first  consider  the  role  played  by  epithehum  in  inflammation, 
and  its  probable  relationship  to  malignant  epithehoma. 


CHAPTER  XLV. 

THE   ROLE   PLAYED  BY  AN  EPITHELIAI-   CELL   IN    INFLAMIVUTION, 
AND  ITS  PROBABLE  RELATIONSHIP  TO  MALIGNANT  EPITHELIOMA.! "-  =» 

Many  of  us  still  have  clear  memories  of  the  pictures  of  cells  described  as  the 
parasites  of  cancer,  and  of  the  rapid  way  in  which  one  view  after  another  found  its 
way  to  the  grave. 

This  activity  was  followed  by  a  spell  of  silence,  broken  by  Unna's  paper,  "  Ueher 
PseudoparasUen  der  Carcinome,"*  and  since  then  the  subject  has  again  passed  into 
oblivion. 

For  many  3'ears,  it  seems  to  have  been  the  custom  to  regard  every  cell,  which 
differed  morphologically  from  the  few  known  fixed  types,  as  a  form  of  degenera- 
tion. 

If  a  cell  degenerates,  surely  its  protoplasm  and  nucleus  will  break  down  into 
the  same  products  as  would  follow  both  its  peptic  and  pancreatic  digestion.  Such 
products  are  chemical  entities,  and  may  be  even  recognised  as  such,  in  the  cells, 
by  micro-chemical  tests.  In  discussing  the  products  of  digestion,  we  never  use  the 
terms  hyaline  or  colloid.  AVhy  should  we  do  so,  when  we  refer  to  the  degeneration  of 
cells  ?  Both  hyaline  and  colloid  are  words  which  mean  nothing,  when  applied  to 
cells,  and  the  sooner  they  are  dropped,  the  sooner  will  histology  be  simplified. 

The  term  hyaline  was  first  employed  by  v.  Recklinghausen,^  and  it  has  been  very 
largely  used  since  by  Unna,*  who  ascribes  to  it  the  following  characteristics  : — 

(1)  It  is  homogeneous  and  highly  refractile,  and  it  differs  from  fibrin  in  not 
splitting  into  fibres  on  digestion. 

(2)  It  is  resistant  to  acids  and  alkalis,  but  will  swell  up  under  the  influence 
of  the  latter. 

(3)  It  is  distinguished  from  the  protoplasm  of  the  cells  from  which  it  arises, 
by  having  a  sharp  contour. 

(4)  It  arises  from,  the  granoplasm  of  the  cells,  especially  from  the  plasma  cells, 
in  the  form  of  either  small  particles  or  balls,  regular  and  irregular  in  shape,  which 
prefer  acid  to  basic  stains. 


502  BIOLOGY   OF   INFLAMMATION   AND    MALIGNANT   DISEASE. 

(5)  It  has  no  relationship  to  the  spongioplasm  of  the  cells,  nor  to  the  nucleus. 

The  above  five  points  hold  good  for  the  so-called  hyaline  masses  of  plasma  cells, 
for  some  of  the  molluscum  bodies,  and  for  a  portion  of  the  stratimi  corneum. 

The  hyaline  masses  of  plasma  cells  result  from  a  breaking  down  of  the  protein 
portion  of  the  protoplasm  of  the  cells.  They  are  distinguished  by  preferring  acid 
to  basic  stains,  by  being  resistant  to  acids  and  alkalis,  and  by  having  a  very  strong 
reducing  action.  The  latter  is  demonstrated  by  the  Berlin  blue  colour  which 
follows  treatment  with  ferri-ferricyanide.  In  between  the  masses  are  often  to  be 
found  strands,  which  no  doubt  form  the  spongioplasm  of  Unna.  These  strands 
have  practically  no  reducing  action  ;  they  prefer  basic  stains,  and  behave  to  reagents 
like  globulin. 

The  reducing  action  of  Unna's  hyaline  masses  is  due  to  tyrosine,  or  tryptophane, 
as  I  showed  in  my  joint  article  with  Mackenzie  Wallis  on  "  The  Chemistry  of  the 
Leucocytozoon  Syphilidis  and  of  the  Host's  Protecting  Cells,"*  and,  in  consequence 
thereof,  we  called  these  masses  Aminoplasma  cells. 

When  stained  in  vivo  with  borax  methylene  blue,  the  aminoplasma  cells  are 
not  broken  up  into  masses,  such  as  one  sees  in  fixed  specimens.  Owing  to  their 
reducing  action,  they  stain  deeply  with  the  methylene  red  moiety  of  the  dye. 

Inside  the  cell,  are  to  be  seen  masses,  strands,  or  fine  filaments,  all  of  which 
stain  deeply  with  the  methylene  violet  moiety.  They  have  nothing  to  do  with 
the  nucleus,  which  has,  as  often  as  not,  disappeared. 

The  portions  of  the  cell  which  stain  with  methylene  violet  are  analogoiis  to, 
and  identical  with,  those  masses  seen  in  the  protoplasm  of  lymphocytes,  and  in 
certain  red  blood  corpuscles.  The  other  structure  which  stains  in  vivo,  in  the  same 
way,  is  the  nucleolus.  Often  in  red  blood  corpuscles,  especially  in  cases  of  severe 
anaemia,  or  in  animals  after  they  have  been  bled,  among  the  dark  blue  masses 
can  be  seen  some  which  take  the  methylene  red  stain.  In  other  words,  some  of 
the  masses  possess  reducing  properties.  There  are  other  substances  which  have  a 
strong  reducing  action  in  addition  to  tyrosine  and  tryptophane,  namely,  fatty  acids. 
Fatty  acids  exist  in  a  cell  in  a  colloidal  complex,  which  is  made  up  of  lecithin  and 
globulin. 

Because  portions  of  certain  red  blood  corpuscles  stain  with  methylene  red, 
and  hence  resemble  the  aminoplasma  cells,  it  must  not  be  assumed  that  the  two 
substances  are  identical ;    in  this  example  they  are  diametrically  opposite. 

The  top  stone  in  the  synthesis  of  a  cell  is  this  lecithin-globulin  adsorption 
compound.  In  the  stone  below,  the  globulin  is  the  same,  but  its  associated  lipoid 
is  less.     In  the  stone  below,  again,  the  globulin  exists  alone. 

That  portion  of  the  aminoplasma  cell  which  stains  in  vivo  with  methylene 


ROLE   PLAYED    BY   EPITHELIAL   CELL.  503 

violet,  in  fixed  specimens,  stains  better  with  pyronin  than  with  eosin,  safranin  or 
acid  fuchsin,  and  hence  is  easily  distinguished  from  the  rest  of  the  cell,  which  stains 
better  with  acid  than  with  basic  dyes. 

The  masses  of  the  aniinoplasma  cell  are  stones  in  the  analysis  of  the  granoplasm 
of  the  cell ;  the  strands,  of  the  spongioplasm  of  the  cell.  My  own  view  is  that 
the  fine  pyroninophile  protoplasm  of  plasma  cells  is  a  colloidal  membrane,  and 
consists  of  a  globulin  in  the  form  of  a  complex  with  a  lipoid  ;  while  that  part  of  the 
protoplasm  under  the  lipoid  envelope  is  albumin. 

Because  it  is  so  difficult  to  tell  when  the  lipoid  envelope  has  disappeared  under 
the  action  of  the  reagent  used,  it  is  impossible  to  test  accurately  by  micro-chemical 
means  the  substance  it  covers.  No  doubt  this  is  the  reason  why  Unna  became  so 
involved  in  all  the  different  kinds  of  albumoses'  which  he  described. 

Personally,  I  do  not  believe  in  the  existence  of  albumoses  in  a  functional  cell, 
but  I  look  upon  them  as  analytic  products  of  proteins,  which  can  be  divided  simply 
into  albumin,  globulin,  and  globulin-lipoid  complexes.  Should  these  degenerate, 
or  become  analysed  below  the  albumose  stage,  in  time  the  amino-acid  stage  is 
reached,  but  it  will  be  reached  more  quickly  in  the  case  of  albumin  than  in  that  of 
globulin,  and  in  the  case  of  globulin  more  quickly  than  in  a  globulin-lipoid  complex, 
with  the  result  that  one  has  no  means  of  telling  whether  one  is  dealing  with  a  pure 
substance  or  not.  I  do  not  for  one  moment  imagine  that  the  so-called  hyaline 
masses  of  plasma  cells  consist  entirely  and  solely  of  amino-acids  ;  other  broken  down 
products  of  protein  digestion  are  surely  also  present ;  but  as  the  tyrosine  is  easily 
demonstrated,  it  seems  better  to  call  them  aminoplasma  cells  than  hyaline  plasma 
cells,  since  the  former  term  denotes  something,  while  the  latter  denotes  nothing. 
The  deduction  that  the  pyroninophile  protoplasm  of  plasma  cells  is  of  the  nature 
of  a  lipoid  envelope,  is  fully  justified  from  my  work  on  the  pyroninophile  protein 
of  the  Leucocytozoon  sypliilidis,^  and  also  from  the  well-known  fact  that,  although 
the  nucleolus  of  a  cell  shows  a  great  affinity  for  pyronin,  it  contains  in  its  interior 
a  mass  of  nucleo-protein.  The  nucleo-protein,  or  nuclein,  consists  of  nucleic  acid, 
and  proteins  which  have  received  the  names  of  histone  and  protamine. 

Doubtless  these  two  substances  are  really  identical  with,  and  indistinguishable 
from,  albumin  ;  therefore,  in  the  nucleus,  we  have  the  same  state  of  afl'airs  as  that 
already  described  in  the  protoplasm  of  the  cell — the  pyroninophile  reducing  substance 
in  the  form  of  a  lipoid  envelope,  the  protein  of  which  is  globulin,  encasing  within  it 
albumin  on  the  one  hand,  and  a  mixture  of  nucleic  acid  and  albumin  on  the  other 
hand.  These  lipoid-globulin  complexes  are  by  no  means  identical,  and  there  is 
a  marked  specificity  about  them,  which  is  explained  better  by  physico-chemical 
than  by  micro-chemical   means.     The  point  to  which  I  wish  to   draw  attention 


50i  BIOLOGY  OF  INFLAMMATION  AND   MALIGNANT  DISEASE. 

here  is,  that  although  all  will  stain  with  both  acid  and  basic  dyes,  some  globulin 
complexes  are  more  acidophilic  than  others,  and  vice  versa. 

Let  me  return  to  what  Unna  calls  the  hyaline  degeneration  of  carcinoma 
epithelium,*  which,  by  the  way,  is  by  no  means  linuted  to  cancerous  tissue.  It 
is  demonstrated  beautifully,  for  instance,  in  Molluscum  contagiosum. 

The  hyaline  degeneration  product  of  epithelial  cells  resembles  the  hyaline 
degeneration  of  plasma  cells,  i.e.,  it  resists  acids  and  alkalis,  gives  the  Berlin  blue 
reaction,  and  prefers  acid  to  basic  stains  ;  but  this  degeneration  product  should 
be  very  carefully  distinguished  from  other  hyaline  bodies,  which  Unna  described 
as  occurring  in  carcinoma — Russell's^  and  Plimmer's'  bodies. 

Although  the  latter  prefer  acid  to  basic  stains,  they  are  far  more  nearly 
amphoteric  than  the  former ;  moreover,  they  are  not  resistant  to  acids  or  alkalis, 
and  they  do  not  give  the  Berlin  blue  reaction. 

It  was  the  omission  of  these  important  tests  which  led  everyone  to  imagine 
that  Russell's*  and  Plimmer's'  bodies  were  cell  degenerations,  and  identical  with 
that  degeneration  witnessed  in  epithelial  cells,  as  in  Molluscum  contagiosum  and 
in  plasma  cells,  as  in  cases  of  verj"  chronic  inflammation ;  especially,  according 
to  my  experience,  in  cases  of  Ehinoscleroma  and  Ulcus  molle  serpiginosum. 

Another  very  important  difference  lies  in  the  fact  that,  in  hyaline  degeneration 
crystal  formation  is  frequently  to  be  observed,  and  this  is  never  the  case  with  the 
bodies  described  by  Russell*  and  Plimmer.' 

The  crystals  may  be  in  the  form  of  sheaths  and  rectangular  prisms,  and  all  I 
can  say  at  present,  is  that  they  are  probably  polypeptides,  because  they  do  not  give 
amino-acid  reactions,  and  the  cell  is  not  so  degenerated  as  the  amino  cell. 

The  past  workers  on  the  cause  of  cancer  may  be  divided  into  two  schools  : 
those  who  thought  that  certain  bodies  which  they  described  were  protozoa,  and 
those  who  considered  those  bodies  to  be  cell  degenerations. 

To  the  former  school  belonged  Plimmer,*  Russell*  and  others ;  to  the  latter 
school  Unna,'  Apolant^"  and  others. 

Unna  says  :  "  Fdrht  sicli  der  Kern  eines  solchen  Gebildes  wie  Chromatin  und 
ist  dabei  punJdfdrmig,  so  Jcann  es  einem  Proiozoon  agnehCu'en :  fdrbt  er  sicli  wie 
Nucleolin,  so  hat  er  audi  wenn  er  nur  jmnktformig  ist,  mit  einem  Protozoon 
nichts  zu  thun,  da  bei  Protozoen  iiberhaupt  keine  KernkOrperchensubstanz 
vorkommt."^ 

This  supposed  difference  does  not  exist.  Hence,  whatever  deductions  Unna 
made  from  his  observations  must  be  false,  as  he  placed  so  much  faith  upon  the 
above  statement.  I  have  already  shown,  by  micro-chemical  means,  what  a 
nucleohxs  is ;    now  let  me  dwell  a  little  upon  its  function. 


ROLE    PLAYED    BY   EPITHELIAL   CELL.  505 

The  nucleolus  is  made  up  of  a  lipoid-globulin  complex,  which  exists  in  the 
form  of  a  colloidal  membrane,  enclosing  nuclein  within  it. 

The  nucleolus  comes  into  greatest  prominence  when  the  cell  is  about  to  divide  ; 
in  fact  it  starts  the  ball  of  division  rolling,  and  is,  to  all  intents  and  purposes, 
entirely  responsible  for  the  process.  The  nuclein  becomes  transformed  into 
chromosomes,  and,  bv  a  process  which  is  too  well  known  to  require  description, 
gives  rise  to  two  nuclei.  It  is  not  always  easy  to  follow  what  happens  to  the 
lipoid-globulin  fraction,  but  a  bright  pyroninophile  spot  is  seen  at  either  pole  of 
the  chromosomes,  and  it  eventually  becomes  the  nucleolus  of  the  newly-formed 
nucleus,  although  it  does  not  take  up  its  central  position  till  later.  The  nucleoli 
are  doubtless  those  centrosomes  which  are  conspicuous  at  the  commencement  of 
cell  division.  This  lipoid-globulin  complex  appears  to  be  the  very  essence  of  life, 
and  is  always  prominent  when  division,  mitotic  or  amitotic,  is  about  to  take  place. 
Note  how  extremely  well  marked  it  is  in  cancer  cells,  where  cell  division  takes  place 
at  a  much  faster  rate  than  normally. 

The  nuclein  of  protozoa  divides  at  a  still  greater  pace,  but  the  results  of 
division  remain  in  the  cell  itself,  until,  in  time,  the  whole  cell  is  filled  with  the 
products  of  this  division,  cf.,  the  changes  from  the  zygote  to  the  spore  cyst.  It 
would  naturally  be  expected  that  the  cell  would  be  rich  in  the  essential  lipoid- 
globulin  compound,  and  that  the  envelope  would  cover  the  whole  cell,  rather  than 
be  limited  to  the  nucleus  only. 

In  the  chapter  on  the  chemistry  of  the  Leucocytozoon  sijpJiilidis,  it  was  shown 
that  the  parasite  consisted  of  an  envelope  which  was  chemically  lecithin-globulin, 
that  this  envelope  had  nuclein  enclosed,  and  that  the  envelope  was  thickest  over 
the  nuclear  area. 

This  envelope  plays  the  part  of  the  nucleolus,  and  becomes  used  up  by  the 
time  the  final  stage  is  reached.  Hence  the  reason  why  the  sporozoites  do  not  show 
such  a  great  affinity  for  pyronin  as  the  zygotes  do. 

Owing  to  the  fact  that  it  has  little  or  no  lecithin-globulin  in  its  structure,  when 
a  sporozoite  takes  upon  itself  to  develop  further,  and  to  start  the  life-cycle  again, 
it  is  obliged  to  enter  a  cell,  in  which  it  has  the  capacity  of  forming  the  compoimd 
from  the  simple  protein  of  the  cell's  protoplasm. 

It  may  be  safely  said  that  the  male  element  has  a  greater  function  to  perform 
than  the  female  one,  partly  owing  to  the  fact  of  its  being  motile.  Therefore  it 
would  be  expected  that  the  male  gamete,  or  Spirochaeta  pallida,  was  richer  in  this 
essential  of  life — lecithin-globulin — than  the  female  gamete.  That  this  is  actually 
the  case  is  seen  from  my  observation  that  the  reducing  action  of  the  female  cell 
becomes  greater  after 'the  entrance  of  the  male.     The  reducing  action  is  due  to 


506  BIOLOGY   OF   INFLAMMATION   AND   MALIGNANT   DISEASE. 

the  fatty  acid  radicle  of  the  lecithin-globuHn  which  the  male  possesses,  and  wliich 
it  imparts  to  the  female  during  the  act  of  impregnation  so  that  division  and 
sub-division  can  go  along  smoothly,  until  the  spores  are  formed.  It  is  highly 
probable  that  the  extreme  richness  of  the  male  gamete  in  lecithin-globulin  is  due 
to  the  fact  that  the  male  gametocyte  develops  intracellularly,  while  the  female 
gametocyte  does  not. 

From  what  has  just  been  said,  it  will  be  noted  that  there  is  already  a  chemical 
relationship  between  the  cancer  cell  and  a  protozoon,  in  that  they  are  both  rich 
in  a  lipoid-globulin  complex.  As  we  proceed,  I  will  endeavour  to  show  that  the 
relationship  is  very  much  closer  still.  Before  describing  those  bodies  which  have  so 
frequently  been  called  the  parasites  of  cancer,  I  would  like  to  draw  attention  to  that 
most  important  clinical  observation,  that  pseudo-chjdous  ascites  may  be  found 
in  patients  suffering  either  from  cancer  or  from  syphilis.i^  i-  This  applies  also  to  the 
finding  of  globulin  in  the  urine.  The  fluid  from  a  case  of  pseudo-chylous  ascites 
is  rich  in  lecithin-globulin,  and  so  is  the  urine  from  that  form  of  so-called  syphilitic 
albuminuria  "syhich  occurs  early  in  the  generahsation  stage  of  syphilis,  and  which 
may  also  be  met  with  in  late  cases  of  the  disease — another  important  similarity 
between  cancer  and  syphihs. 

The  Description  of  the  so-called  Parasites  of  Cancer. 

Hitherto  these  bodies  have  been  looked  upon  as  protozoa,  which  had  entered 
the  cells  of  their  host,  and  as  nuclear  degenerations. 

They  are  neither  ;  and  if  the  illustrations  are  closely  followed  it  will  be  seen 
how  these  bodies  arise.  In  short,  they  develop  from  the  nucleoli.  In  Plate  43  (1)  A, 
(stained  with  pyronin  and  methyl  green)  a  nucleolus  is  seen  leaving  the  nucleus  of 
an  epithelial  cell.  B  shows  the  nucleolus  almost  outside  the  nucleus.  C  shows 
a  nucleolus  which  has  become  transformed  into  pigment.  This  will  be  referred  to 
again,  but  I  wish  to  direct  attention  to  the  nucleus  on  the  left.  The  nucleus  has 
divided  :  one  half  contains  a  nucleolus  ;  the  other  half  has  expelled  the  nucleolus, 
which  has  become  pigmented. 

The  expelled  nucleolus  consists  of  a  lecithin-globulin  envelope,  enclosing  some 
nuclein.  The  nucleolus  increases  in  size,  until  a  cell  is  seen  which  can  be  divided 
into  two  parts— protoplasm  and  a  nucleus  (vide  Plate  44  (1 )).  The  resemblance  of  this 
cell  to  the  syphilitic  female  gametocyte  is  very  close,  and  it  stiU  further  resembles 
it  chemically,  in  that  the  nucleus  is  covered  by  a  Upoid-globiilin  structure,  which, 
owing  to  its  reducing  action,  prevents  the  nucleus  from  staining  ^ith  methyl  green. 

On  Plate  44  (2,  3)  are  two  pseudo-parasitic  cells,  in  which  the  lipoid-globulin 
envelope  has  disappeared,  and  this  allows  the  nucleus  to  stain  in  the  ordinary  way. 


Plate  43. 


Section  of  a  malignant  ijrickle-celled  epithelioma,  stained  with  pyronin 
and  methyl  green. 

A.  A  nucleolus  is  to  be  seen  leaving  the  nucleus  of  an  ipithelial  cell. 

B.  The  nucleolus  is  now  almost  outside  the  nucleus. 

C.  The  nucleolus  has  become  transformed  into  pigment. 

D.  A  pseudo-parasitic  body,  which  has  become  transformed  into  pigment. 

2. 

Section  of  a  malignant  prickle-celled  epitheUoma  (same  case  as  aliove), 
stained  with  Ehrlich's  triacid  mixture. 

A,  B,  C,  D,  E,  P.  Show  pseudo-parasitic  bodies  in  various  stages  of 
development.  Each  one  has  arisen  from  a  nucleolus  of  an  epithelial 
cell.  The  lecithin-globulin  portion  of  the  nucleolus  has ,  become 
the  protopla.smic  part,  and  the  nuclein  portion,  the  nuclear  part  of 
the  pseudo-parasitic  cell.  It  will  be  seen  that  the  pseudo-parasitic 
lipoid-globulin  shows  a  marked  affinity  for  acid  fuchsm. 


m 


m 


Pl^TE  43. 

Facing  p.  608. 


.i)t; 


•odies  \\L 
•  ..^wt'iiA  ■  vv  attention  ' 

I,  that  pseu. 

,r  ■j-sHohq  IjciJBU'i 

J   case,  oi  ij'fT 

.^^)^^g  J^riJam  bra; 

Ju^insiq  ■  i^imiJ  3fjioo'3i(  ejifl  rioid-w  .vfxjd  oiJi>.ciJi(j-ol)i/oaq  A  .(I 


,(   vii  ■;    ^1,  oKjio  erne?.)  empil'iiitiq^i  boll^o-abbhq  JriJsXii^il^fn  is  lo  (ioi)ao<< 

*      ' '  '  .aiutzim  biochif  a'lloil'ija  di'ni  I)3ni,Bia 

io  gejcta  auohcv  ni  aaibod  9E)i«ii«q-obiJ9aq  woil8  .1  ,H  ,Q[  ,0  ,8  ,A 
Ijjiiejidiqs  aa  in  eiiiooloiiti  e  moil  apuii^  aed  aoo  dsf^^jh-^xi^aicprfay^H 
^moood  ?Jid  mitosloua  odi   io  (loWioq^  aijifdolg-njfffeal  «dT-ij.iI' 
lo  :fi/;q  melbna  orfi  ,noiJioq  nialoDfi  adJ  bnc  ,ixBq  oiifiKisIqoioiq  odi 
oilfeiii^q-obtiapq  arii  issii  ti9&s')d''Vhf  it'^.O^'oMkihsq-dfitn^qodi 
.HierioolbioBiOl  ^i*iBiSifl  lMQJtfitfiis»'^afih)d6iniIiJcfeIg*bioqiJ  ' 

%vili  be  referred  to 
The  nuclcnv  v.,, 

1  the  nu! 


■11  furtlier  re^ 
obulin  struct 


ain  in  the  G^^imw*"* 


■V, 

Platb  43. 


f^      / 


«  Platk  44.  .  i 

Pseudo-parasitic  bodies  from  a  case  of  malignant  prickle-celled  epithelioma. 


Plate  44. 

FoUom  Plate  43. 


.4  t  in  A.l'T 
.tiiiioiJ^iliiqo  balbo-oldoiiq  iaeir^ilem  lo  oseo  ts  moil  esibod  oiliaJtifiq-obiree*! 


,8J.  »U>J1  »)H>VW4 


tl 


•M.  ♦' 


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10. 


« 


11. 


^•* 


12. 


14. 


13. 


Plate  44. 


EOLE    PLAYED    BY   EPITHELIAL   CELL.  507 

The  nucleus  of  the  pseudo-parasite  differs  from  that  of  a  protozoon  in  one  respect,  in 
that  it  can  divide  by  mitosis ;  but  resembles  it  in  the  other  respect,  in  that  it  can 
also  divide  by  amitosis  or  after  the  budding  fashion. 

Plate  44  (4,  5)  demonstrates  the  former — division  by  mitosis. 

Plate  44  (6,  7)  demonstrates  the  latter — division  by  amitosis. 

Note  how  closely  Plate  44  (7)  resembles  the  spore  cyst  in  syphilis. 

Plate  44  (6,  8)  represents  specimens  specially  treated  with  boric  acid,  which 
dissolves  out  the  albumin  of  the  cell,  but  leaves  the  globvdin.  In  Plate  44  (6)  it  will 
be  seen  that  the  protoplasm  of  the  cell  has  vanished,  that  the  nucleus  has  divided 
into  two,  but  that  it  refuses  to  stain  with  methyl  green,  owing  to  the  lipoid-globulin 
membrane  which  still  covers  it.  A  mass  of  this  protein  complex  is  also  seen  between 
the  two  portions. 

In  Plate  44  (8)  the  nucleus  is  uncovered,  but  two  masses  of  lipoid-globulin 
exist  in  the  cell. 

This  uneven  distribution  of  the  lecithin-globulin  at  once  distinguishes  these 
cells  from  protozoa.  Moreover,  it  is  not  in  such  quantity,  nor  so  resistant  to  reagents, 
as  that  found  in  the  Leucocytozoon  syphilidis,  for  instance. 

The  nucleolus,  which  becomes  the  pseudo-parasite,  need  not  necessarily  be 
discharged  from  the  cell.  It  may  develop  in  the  protoplasm  of  the  epithelial  cell, 
as  in  Plate  44  (9),  or  in  the  nucleus,  as  in  Plate  44  (10),  or  in  a  part  of  the  nucleus,  as 
in  Plate  44  (11)  How  close  is  now  the  resemblance  to  the  Plimmer*  and  Russell* 
bodies.  Plate  43  (2)  is  stained  with  Ehrhch's  triacid  stain,  in  order  to  show  the 
strong  affinity  which  the  protoplasm — or,  to  be  more  accurate,  the  lecithin- 
globulin — of  the  pseudo -parasites  shows  for  acid  fuchsin. 

Plate  44  (12)  shows  pigment  formation,  in  the  protoplasm  of  an  epithelial  cell. 
Plate  44  (13)  shows  pigment  in  the  process  of  production  in  a  pseudo-parasitic 
cell,  and  Plate  44  (14)  shows  a  further  stage  of  the  proceeding,  which  is  also 
demonstrated  by  D  in  Plate  43  (I). 

This  pigment  is  not  haemosiderin,  and  it  differs  from  the  ordinary  melanin 
of  the  epithehum  in  being  insoluble  in  hydrogen  peroxide,  bromine  water,  acids, 
and  allcaUs.     It  forms  BerUn  blue  from  ferri-ferricyanide,  and  it  is  highly  probable  • 
that  it  related  to  tvrosine,  and  is  dependent  upon  an  oxydase  reaction. 

The  formation  of  pigment  from  globulin  is  well  known,  but  its  exact  chemical 
nature  is,  as  yet,  unsolved.  A  fluid  containing  lecithin-globulin,  a  urine  for  instance, 
may  suddenly  go  jet  black,  and  the  pigment  formed  is  resistant  to  every  reagent. 
Therefore  it  is  quite  distinct  from  haemosiderin,  and  it  does  not  quite  conform  to 
melanin,  as  it  is  generally  known.  I  have  particularly  called  attention  to  this 
pigment  for  two  reasons.     First,  because  it  develops  fi-om  globuHn,  which  supports 


508  BIOLOGY    OF   INFLAMMATION   AND    MALIGNANT   DISEASE. 

my  chemical  investigations  into  the  psendo-parasites  ;  secondly,  because  it  is  rare 
in  malignant  epitheliomata. 

Without  recapitulation,  it  will  be  seen  how  close  is  the  resemblance  between 
these  pseudo-parasites  of  cancer  and  protozoa,  the  great  and  important  difference 
lying  solely  in  the  nature  and  distribution  of  the  lipoid-globulin.  The  lipoid- 
globulin  of  the  cancer  cells  is  less  organised,  shows  a  greater  affinity  for  acid  than 
for  basic  dyes  than  does  that  of  the  syphilitic  parasite,  and,  furthermore,  it  has  not 
such  a  strong  reducing  action  as  has  the  latter. 

From  what  I  have  already  stated,  it  will  at  once  be  clear  to  the  reader  in  what 
respects  cancer  differs  from  an  infection ;  for  instance,  from  syphilis.  A  cancer  cell 
has  less  lecithin-globulin ;  its  division  cannot  proceed  so  rapidly,  and,  when  the 
lecithin-globidin  is  exhausted,  the  cell  is  entirely  used  up,  as  the  nuclein  left  behind 
cannot  enter  another  cell  and  start  a  cycle  again.  I  do  not  wish  to  infer  that  the 
life  history  of  cancer  is  always  similar  to  what  I  have  described,  as  plain  nuclear 
division  and  sub-division  may  be  all  that  is  seen,  and,  in  fact,  in  Plate  43  (1)  this 
multiplication  of  the  nucleus  is  clearly  depicted. 

All  variations,  from  simple  nuclear  division,  to  the  formation  of  nucleolar 
pseudo-parasitic  bodies,  exist  in  both  carcinomata  and  sarcomata,  and  a  study  of 
the  nucleolus  in  a  doubtful  section  is  of  much  greater  value  than  determining 
whether  the  growth  is  infiltrating  or  not. 

All  cases  vary  in  the  degree  of  the  transformations  undergone  by  the  nucleoli. 
It  may  be  as  regular  as  I  have  depicted  in  the  accompanying  figures,  or  so  irregular 
that  a  description  would  be  impossible.  The  reason  why  I  have  chosen  these  clear 
forms  to  discuss  is,  partly  because  it  has  been  suggested  that  the  phases  I  described 
of  the  life  history  of  the  organism  of  syphilis  were  the  same  bodies  as  Plimmer  and 
Kussell  described  in  cancer,  and  partly  because  I  wanted  to  prove  how  valuable 
Plimmer's  and  Russell's  observations  were,  arid  what  a  mistake  it  was  to  class  the 
bodies  described  as  nucleai'  degenerations,  withoiit  doing  more  work  on  the  subject. 

I  cannot  help  feeling,  in  my  own  nund,  that  there  is  no  one  and  specific  cause 
of  cancer,  but  that  as  inflammation  is  the  result  of  an  infection,  and  inflammation 
can  precede  a  cancer ;  therefore,  both  inflammation  and  cancer  are  two  links  in  a 
chain  of  events  which  result  from  no  one  specific  cause,  and  therefore,  this  chain 
represents  a  sequence  of  events  in  the  protective  mechanism  of  the  body  against 
that  cause. 

In  inflammation  of  the  skin,  the  epithelium  plays  a  very  important  part.  Note 
the  so-called  acanthosis  in  warts,  which  not  infrequently  become  malignant.  A 
hypertrophy  of  the  stratum  malpighii  is  the  rule  in  many  syphilitic  and  tubercular 
affections  of  the  skin,  and  there  are  plenty  of  cases  on  record,  in  which  malignant 


ROLE    PLAYED    BY    EPITHELIAL   CELL.  509 

epitheliomata  have  occurred  on  Lupus  vulgaris  and  guminata.  I  have  seen  even 
a  primaiy  syphilitic  lesion  become  mahgnant,  indeed  I  have  had  two  cases  recently 
under  my  care. 

The  epithelium  takes  part  in  the  inflammation  caused  by  the  sun's  rays  and 
by  X-rays,  and  to  show  how  commonly  mahgnant  epithehomata  result,  one  need 
only  mention  Kaposi's  disease  Xerodermia  pigmentosa,  if  an  example  is  required. 

I  hold  that  cancer  is  not  an  entity,  but,  with  inflammation,  and  the  inter- 
mediary stages  between  the  two,  it  forms  a  link  of  a  chain,  which  one  may  call  the 
protective  mechanism  of  the  body  against  all  enemies.  Therefore,  if  my  theories  be 
correct,  there  is  no  one  single  cause  of  malignant  disease. 

All  we  can  say  is,  that  cancer  will  result,  should  one  of  the  enemies  of  the  host 
be  powerful  enough  to  make  the  host  cells  form  more  than  the  usual  amount  of  a 
certain  chemical  substance,  which  is  of  the  nature  of  a  lipoid-globulin  adsorption 
compound. 

Summary. 

1.  That  the  pseudo-parasites  of  malignant  epithelioma  are  transformations 
which  the  nucleoli  have  undergone,  to  protect  the  host  against  some  uncertain  cause. 

2.  That  the  pseudo-parasites  are  neither  true  parasites,  because  they  do  not 
behave  as  such,  nor  are  they  cell  degenerations,  because  they  consist  chemically  of 
a  very  highly  complex  body,  lecithin-globulin. 

3.  That  chronic  inflammation  may  start  the  production  of  these  bodies,  and 
that  a  relationship  exists  between  inflammation  and  malignant  disease. 

4.  That  this  relationship  may  be  followed  in  its  different  phases  which  con- 
stitute the  links  of  a  chain,  which  may  te  called  for  convenience  the  "  epiblastic 
chain." 

I  will  now  pass  on  to  a  classification  of  the  cutaneous  epitheliomata,  and  will 
close  this  chapter  with  a  description  of  them. 

A  Classification  of  the  Cutaneous  Epitheliomata. 

Before  proceeding  to  draw  up  a  classification  of  the  cutaneous  epitheliomata, 
we  must  first  of  all  banish  the  difference  of  meaning  which  the  word  epithelioma 
possesses  in  this  country  and  on  the  Continent. 

The  word  epithelioma  clearly  means  a  tumour  of  epithelium,  and  there  is 
nothing  in  the  word  to  suggest  mahgnancy.  Therefore,  the  Continental  meaning 
of  the  word  is  the  con^ct  one. 

Epithelioma  alone  should  signify  merely  a  growth  of  epithelial  tissue,  and  a 


510  BIOLOGY    OF   INFLAMMATION   AND   MALIGNANT   DISEASE. 

prefix  slioiild  be  added,  when  it  is  required  to  state  what  kind  of  epithelial  tissue 
is  referred  to. 

Prickle-celled  epithelioma  would  mean  an  epithelioma  beginning  in  the 
stratum  malpighii,  and  the  nature  of  the  growth,  whether  innocent  or  not,  could 
be  told  by  putting  the  word  benign  or  malignant  in  front. 

A  rodent  ulcer  would  become  basal-celled  epithelioma  ;  an  epithelioma  of  the 
hair  follicles,  trichoepithelioma  ;  of  the  sebacous  glands,  sebaceous  epithelioma  ; 
of  the  sweat  glands,  syringoepithelioma. 

Intermediary  types,  maybe  differing  both  clinically  and  histologically  from 
the  groundwork  types,  and  linking  up  the  latter  into  a  chain,  which  will  be  described 
later,  might  still  receive  the  name  which  the  first  describer  gave  to  them. 

Beginning  with  the  prickle-celled  epitheUoma,  we  have  the  common  benign 
papilloma,  in  which  the  cells  still  retain  their  prickles  ;  we  then  come  to  a  peculiar 
form  of  papilloma  which  is  clinically  indistinguishable  from  the  simple  papilloma, 
but  differs  from  it  in  that,  even  if  it  is  widely  removed,  it  will  recur  in  situ,  and 
others  may  appear  in  different  parts  of  the  body.  The  growths  neither  spread 
nor  ulcerate,  nor  do  they  have  metastases.  Histologically,  more  epitheUal  tissue 
is  seen  in  this  than  in  a  simple  papilloma,  and  in  some  cases  it  is  extremely  difficult 
to  say  whether  the  epithelial  tissue  is  invading  healthy  tissue  or  not.  The  epithelial 
cells  are  not  so  well  formed  as  those  met  with  in  a  simple  papilloma,  and,  moreover, 
prickles  are  not  discernible.  The  type  should  receive  the  name  of  benign  reciuring 
prickle-celled  epithelioma.  Not  infrequently,  more  than  one  member  of  the  family 
is  affected  with  this  t^-pe  of  growth. 

We  come  next  to  the  pure  basal-celled  epithelioma,  or  rodent  ulcer,  and  between 
this  and  the  maHgnant  prickle-celled  epithelioma,  with  its  typical  cell  nests  of  horny 
material,  all  grades  of  epitheliomata  exist,  which  vary  according  to  the  layer  or 
layers  of  epithelium  from  which  the  growth  originates. 

The  epithelioma  following  X-rays  is  an  epithelioma  of  the  uppermost  layers 
of  the  stratum  malpighii,  hence  the  enormous  richness  of  cell  nests.  The  epithelioma 
following  the  sun's  rays  is  an  epithelioma  of  the  lowest  layers,  including  the  basal 
cell  layer ;  hence  many  have  the  histological  features  of  a  rodent  ulcer,  but  they  differ 
from  it,  in  that  cell  nests  can  usually  be  found.  Cell  nests,  then,  in  a  section  which 
resembles  a  rodent  ulcer,  merely  mean  that  layers  of  epithelium  above  the  basal 
cell  layer  have  been  implicated.  Therefore,  a  sharp  distinction  between  malignant- 
squamous-celled  epithelioma  and  rodent  ulcer  does  not  exist ;  reh-ing  upon  the 
absence  or  presence  of  cell  nests  to  clear  the  diagnosis  is  unjustifiable,  as  all  grades 
between  the  two  may  occur. 

AVe  can  now  pass  on  to  the  new  growths  of  the  epithelial  appendages. 


ROLE    PLAYED   BY    EPITHELIAL   CELL.  51  I 

The  trichoepithelioma,  the  so-called  sebaceous  adenoma  and  syringoma,  are 
typical  epitheliomata  of  specialised  epithelial  cells.  These  tumours  all  have  a  point 
in  common,  in  that  they  are  mostly  very  benign,  do  not  even  tend  to  increase 
in  size,  and  do  not  ulcerate.  Mahgnant  trichoepithelioma  does  not  exist,  though 
theoretically,  there  is  no  reason  why  it  should  not ;  recurrent  syringoepithelioma 
is  excessively  rare,  but  recurring  sebaceous  epithehoma,  although  rare,  is  occasionally 
met  with.     Very  rarely  a  mahgnant  sebaceous  epithehoma  may  be  met  with. 

The  groundwork  cells  of  the  epithelial  appendages  are  the  same,  and  it  is  not 
until  they  near  the  stage  of  maturity,  that  one  can  say  that  this  group  of  cells  is  to 
form  hair  follicles,  and  that  group  sebaceous  glands,  and  the  other  group  sweat 
glands.  Now,  new  growths  of  these  groundwork  cells  can  occur  ;  a  tumour  may 
arise  just  when  the  epithelial  cells  are  on  the  point  of  setting  ofE  cells  destined  to 
form  the  appendages,  when  the  histological  appearances  will  closely  resemble  a 
rodent  ulcer. 

On  the  other  hand,  a  tumour  may  arise  when  the  cells  which  have  been  set 
ofE  have  become  so  specialised  as  to  be  almost  distinguishable  as  lanugo  hair  follicle 
cells.  Between  the  two,  all  grades  of  tumours  may  be  met  with.  The  most 
embryomc  tumour  is  the  so-called  multiple  rodent  ulcer,  and  the  more  mature 
tumour  is  the  so-called  Epithelioma  adenoides  cysticum. 

If  sections  from  different  cases  of  these  two  types  of  tumour  are  examined,  it 
will  be  found  that  no  two  are  exactly  alike;  in  one,  the  resemblance  to  rodent  ulcer 
may  not  be  so  marked,  and  in  the  other,  it  would  be  stretching  the  imagination  to 
say  that  the  tumour  had  anything  to  do  with  the  lanugo  hair  follicles. 

Whether  a  tumom-  is  benign  or  malignant  depends,  in  my  mind,  partly  upon 
the  stage  in. the  development  of  the  cells  from  which  the  tumour  arises,  and  partly 
upon  the  resistance  of  the  cells  involved,  against  the  exciting  cause.  In  very  early 
embryonic  life,  the  epidermis  consists  of  one  layer  of  epithelium,  the  cells  of  which 
resemble  the  later  basal-celled  layer  or  stratum  spinosum. 

Therefore,  a  tumour  arising  therefrom  will  have  a  great  capacity  for  activit}^ 
or,  in  other  words,  malignancy,  while  tumours  arising  from  mature  and  highly 
speciahsed  sebaceous  gland  cells — cells  which  have  reached  their  zenith,  or  have 
performed  their  function — have  httle  or  no  capacity  lor  activity,  and  therefore 
are  benign.  As  the  term  malignant  is  apphed  to  the  activit}^  just  referred  to,  as 
well  as  to  the  pseudo-parasitic  development  of  nucleoh,  it  would  be  better  to  reserve 
the  term  for  the  latter,  and  to  call  the  former  merely  "  embryonic  activity." 

Tumours  arising  from  cells  in  their  intermediate  stages  are  neither  so  active, 
and  therefore  malignant,  as  the  former  group,  nor  so  mature  and  benign  as  the  latter 
group,  so  they  are  able  to  recur  only  after  removal. 

2k 


512  BIOLOGY    OF   INFLAMMATION    AND    MALIGNANT    DISEASE. 

However  active  or  embryonic  cells  may  be,  a  tumour  arising  therefrom, 
whatever  its  dimensions,  will  still  consist,  morphologically,  of  the  same  cells,  or,  in 
other  words,  the  cells  constituting  the  growth  do  not  become  more  mature  or 
specialised. 

It  will  now  be  best  to  append  my  classification  of  the  cutaneous  epitheliomata, 
and  then  to  describe  more  fully  each  of  the  chief  types  met  with.  The  cutaneous 
epithehomata  should  be  divided  into  three  main  groups  : — 

1.  Epidermic. 

2.  Appendicular. 

3.  Mixed  epidermic  appendicular. 

The  epidermic  class  should  be  divided  up  into  prickle-celled  epithelioma,  mixed- 
celled  epithelioma,  and  basal-celled  epithelioma.  The  prickle-celled  epitheliomata 
should  be  further  subdivided  into  benign  prickle-celled  epithelioma  or  papilloma, 
recurring  prickle-celled  epithelioma,  and  malignant  prickle-celled  epithelioma. 

The  appendicular  class  should  be  divided  into  trichoepithelioma,  sebaceous  epi- 
thelioma, and  syringoepithelioma,  the  two  last  having  a  subdivision  of  recurring 
sebaceous  epithelioma,  and  syringoepithelioma. 

The  mixed  epidermic  appendicular  class  should  be  subdivided  into  multiple 
rodent  ulcer,  and  EpitJielioma  adenoides  cysticum. 

A  Description  of  the  Embryonic  Cutaneous  Epitheliomata. 

Concerning  most  of  the  epitheliomata  of  the  skin,  there  are  four  very  striking 
points,  to  which  I  was  the  first  to  refer  : — 

1.  The  mixture  of  types.  By  the  side  of  a  rodent  ulcer,  a  sebaceous  epithelioma 
is  not  at  all  uncommon.  Most  sebaceous  and  syringoepitheliomata  are  accom- 
panied by  trichoepitheliomatous  elements.  A  combined  sebaceous  and  s3rringo- 
epithelioma  is  not  at  all  imcommon.     Clinically,  there  is  no  differentiation. 

2.  The  almost  constant  occurrence  of  milia. 

3.  The  predilection  which  the  tumours  have  for  the  oculo-facial  and 
naso-facial  grooves. 

4.  The  frequent  occurrence  of  mole  or  naevus  cells  (endothehal  cells)  in  the 
more  embryonic  types  of  growths. 

It  must  have  struck  man}',  how  frequently  new  growths  of  the  face  have 
occurred  in  the  oculo-facial  and  naso-facial  folds.  There  is  scarcely  a  human  being 
whose  skin,  below  the  lower  eyelid  or  at  the  junction  of  the  nose  and  the  cheeks, 
when  carefully  examined,  does  not  reveal  the  appearance  of  several  small  glands, 
some  of  which  may  be  so  enlarged  as  to  be  pathological. 


ROLE    PLAYED    BY    EPITHELL\L   CELL. 


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514  BIOLOGY   OF   INFLAMMATION    AND   MALIGNANT   DISEASE. 

The  mere  fact  that  the  looseness  of  the  skin  over  this  area  makes  the  under- 
lying structures  more  apparent,  will  not  account  for  the  phenomenon,  the  explana- 
tion being  forthcoming,  only  when  the  same  regions  in  the  lower  mammaha  are 
studied. 

If  a  microscopical  examination  of  the  skin  at  the  base  of  the  lower  eyelid  is 
made,  it  will  reveal,  in  almost  every  individual,  specialised  embryonic  epithelial 
structures,  as  lanugo  hair  follicles,  sweat  glands,  and  sebaceous  glands. 

On  a  larger  scale  they  may  be  considered  pathological,  and,  when  the  growth 
is  limited  to  the  lanugo  hair  follicles,  the  term  Trichoepithelioma  may  be  applied, 
when  to  sebaceous  glands.  Sebaceous  adenoma,  and  when  to  sweat  glands, 
Si/ringoma. 

The  tumour  may  consist  of  any  one  of  these,  alone  or  mixed,  and,  when  mixed, 
the  different  types  may  be  present  in  the  same  area,  or  a  type  may  be  found  pure 
in  one  part  of  the  section,  and  another  type  pure  in  another  part  of  the  section. 

None  of  these  types  increase  in  size,  ulcerate,  or  become  malignant,  for  the 
simple  reason  that  they  consist  of  nearly  mature  epithelial  cells,  or  perhaps  it  would 
be  better  to  say,  cells  which  cannot  wander  from  a  special  form,  because  they  have 
arrived  at  that  stage  when  a  function  has  been  appointed  them,  and  because  they 
occur  in  tissue  in  which  they  normally  would  be,  viz.,  corium.  This  is  not  the 
case  with  rare  tumours,  which,  when  present,  are  common  in  the  situations  under 
discussion,  viz..  Epithelioma  adenoides  cysticum,  and  Ulcus  rodens  multiplex.  The 
swellings  not  only  increase  in  size  up  to  a  certain  point,  they  also  ulcerate,  but 
without  extending  further,  or  giving  rise  to  metastases.  The  cells  of  the  tumours 
are  epithelial  in  origin,  but  whether  of  the  type  destined  to  be  hair-folhcles 
or  sweat  glands,  etc.,  cannot  alw^ays  be  ascertained,  since  in  some  cases  the 
cells  have  not  arrived  at  the  stage  when  they  are  to  serve  a  purpose,  i.e.,  they 
are  more  embryonic  than  the  cells  of  the  trichoepithelioma,  sj'ringoma,  etc. 
Still  more  is  this  the  case  with  a  tumour  which  is  most  commonly  situated  in 
the  orbito-facial  and  naso-facial  folds,  and  which,  once  it  has  ulcerated,  tends  to 
spread  and  destroy  all  the  structures  in  the  neighbourhood,  but  without  giving 
rise  to  metastases  or  glandular  enlargements — the  so-called  Ulcus  rodens.  The 
controversy  as  to  the  origin  of  a  rodent  ulcer,  whether  it  arises  from  the  inner  root 
sheath  of  the  hair  follicle,  or  at  the  point  of  exit  of  the  sebaceous  gland  into  the 
hair  folhcle,  because  the  cells  are  spindle  in  form,  seems  so  much  waste  of  energy, 
as  the  cells  constituting  a  rodent  ulcer  are  embryonic  epithelial  cells  of  a  very  early 
type,  when  the  spindle  shape  is  the  rule  rather  than  the  exception  ;  the  cells  being 
laid  down  at  a  time  when  hair  follicles  and  sebaceous  glands,  etc.,  are  unthought  of. 
"When  development  takes  place  in  an  area  in  which  the  structures  have  matured, 


Section  tlii'oug-li  ;i  ililiuiii. 


Triclioppitlielioma  I'.-i[iuI.isum. 


Plate  45. 


Fuciwj  p.  514. 


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Folhirs  Plate  45. 


ROLE   PLAYED    BY    EPITUELIAL   CELL.  515 

and  in  tissue  in  which  they  are  not  wont  to  occur,  the  cells  grow  in  a  peculiar  way, 
and  so  constitute  what  I  have  called  embryonic  activity. 

The  presence  of  cell  nests  in  a  rodent  ulcer  have  raised  many  difficulties,  both 
as  regards  the  diagnosis  between  a  rodent  ulcer  and  squamous-celled  epithelioma, 
and  as  regards  the  origin  of  the  former ;   but  quite  unnecessarily. 

Characters  typical  of  an  epithelioma  may  be  found  alongside  a  rodent  ulcer, 
but  not  vice  versa,  and  the  explanation  lies,  no  doubt,  in  the  fact  that  the  rodent 
ulcer  acts  as  an  irritant,  and  so  causes  an  abnormal  epithelial  growth  with  cell- 
nests,  as  occurs  in  a  skin  exposed  to  the  sun's  rays  or  to  X-rays.  Again,  small  horny 
nests  may  be  found  in  the  rodent  ulcer  tissue  itself,  but  it  will  be  noticed  that  the 
cells  around  are  cubical,  more  like  the  normal  rete  cells  than  like  the  typical  spindle 
cells.  The  epidermis  primarily  consists  of  one  layer  of  spindle  cells,  and  from  this 
layer  other  cells,  cubical  in  form,  arise,  and  these  in  turn  become  transformed  into 
horny  tissue,  at  quite  an  early  stage  in  embryonic  existence,  before  hair  follicles  and 
other  specialised  epithelial  structures  are  considered.  Then  is  it  not  possible  that 
such  rodent  ulcers  arise  from  rests  of  a  later  date,  when  the  cells  have  already  learnt 
the  transformation  into  horny  tissue  ? 

A  concomitant  feature,  in  nearly  all  cases  of  growths  from  these  regions,  is  the 
presence  of  milia  (Plate  45  (1)).  How  are  these  tiny  round  hard  white  swellings 
formed  ?  Opinions  differ  widely.  They  shell  out  on  incising  the  covering  skin, 
and,  under  the  microscope,  appear  as  cysts  filled  with  some  homogeneous  substance. 
No  doubt  they  are  formed  in  various  ways  :  (1)  From  a  dilated  lanugo  hair 
follicle.  Plate  46  shows  this  admirably.  This  is  a  case  of  a  rodent  ulcer,  in  the 
surrounding  inflammatory  tissue  of  which  is  seen  a  typical  milium,  to  which  is 
attached  part  of  a  sebaceous  gland,  and  below  is  the  hair  root  with  its  papilla. 
(2)  From  a  dilated  sweat  duct :  Schidachi  was  able  to  produce  sweat  gland  cysts 
by  shaving  off  a  piece  of  skin  from  the  pad  of  a  cat's  foot  parallel  to  the  surface, 
stretching  the  same,  and  then  laying  it  back  to  let  it  grow.  As  the  sweat  ducts 
did  not  overlap,  cysts  were  produced.  (3)  From  an  epidermic  inclusion,  which  has 
become  cystic,  since  they  occur  in  skin  which  has  formed  over  a  burn,  in  the  new 
skin  which  develops  after  a  bulla,  in  pemphigus.    Epidermolysis  bullosa,  etc. 

I  will  now  mention  a  typical  case  of  each  type  of  epithelial  growth  referred  to 
above. 

Case  80. — Trichoepithelioma  papuhsum. — E.  D.,  aged  48  years,  housewife, 
came  up  to  St.  Bartholomew's  Hospital  complaining  of  a  scaly  eruption  on  her  right 
shin.  She  was  also  noticed  to  have  some  pale,  slightly  raised  nodules  on  her  face. 
When  attention  was  drawn  to  these  the  patient  said  that  they  were  of  no  moment, 
gave  rise  to  no  inconvenience,  and  that  she  had  had  them  for  years. 


516  BIOLOGY    OF   INFLAMMATION    AND    MALIGNANT   DISEASE. 

These  nodules  were  about  the  size  of  a  lentil,  about  ten  in  number,  and  situated 
on  the  lower  border  of  the  lower  eyelid,  and  extending  from  the  inner  to  near  the 
outer  canthus,  where  they  somewhat  decreased  in  number  and  size. 

Both  sides  of  the  face  were  equally  affected.  One  or  two  nodules  were  found 
on  the  upper  eyelid,  and  at  the  outer  canthus  there  were  a  few  milia.  Each  lesion 
was  about  the  size  of  a  lentil,  circular,  very  slightly  raised  above  the  level  of  the 
skin,  flat  on  the  surface,  and  the  skin  covering  them  was  paler  than  it  was  elsewhere. 

They  felt  hard,  did  not  disappear  on  pressure,  but  became  quite  white.  Patient 
said  she  had  had  them  as  long  as  she  could  remember,  but  she  believed  they  first 
appeared  when  she  was  14  or  15  years  of  age. 

The  mother  and  one  sister  had  the  same  condition.  Three  other  sisters  were 
free. 

There  was  no  history  of  any  male  member  of  the  family  being  affected. 

A  nodule  was  excised  for  microscopical  examination  (Plate  45  (2)). 

The  epidermis  is  flattened,  all  papillary  arrangement  has  disappeared. 

The  number  of  layers  of  the  epidermis  is  somewhat  smaller  than  normal,  but 
the  gradual  transition,  from  the  basal  cell  layer  to  the  stratum  corneum,  remains 
intact. 

The  basal  cell  layer  is  pigmented  more  than  usual. 

Along  the  epidermis,  processes  are  to  be  seen  dipping  down  into  the  coriuin  ; 
each  process  is  cystic,  the  space  being  filled  with  horny  material,  in  the  centre  of 
which  lies  a  lanugo  hair.  Oddly  enough,  in  some  of  the  cysts  acne  bacilli  are  to  be 
seen.  These  have  probably  penetrated  from  the  surface,  and  might  have  had  some- 
thing to  do  with  stimulating  the  growth  formation.  Notice  the  age  at  which  the 
tumours  occurred,  the  age  when  acne  most  commonly  commences. 

In  places  where  the  lanugo  hair  has  been  able  to  penetrate  the  epidermis,  it  is 
surrounded  with  several  layers  of  horny  material,  having  the  arrangement,  as  seen 
in  a  transverse  section,  of  an  onion  through  its  middle.  Around  these  epidermal 
processes,  there  is  no  cellular  infiltration  (inflammation).  In  the  corium  are  numerous 
hair  follicles,  all  of  which  are  cystic. 

The  walls  show  the  transition  stages  from  the  stratum  spinosum  to  the  stratum 
corneum,  as  is  seen  in  the  epidermis,  with  the  only  difference  that  the  basal  cell 
layer  remains  quite  free  from  pigment. 

In  the  centre  is  a  mass  of  horny  material ;  distinct  cells  are  to  be  seen  con- 
taining eleidin  granides. 

In  the  centre  of  each  horny  cyst,  a  lanugo  hair  is  to  be  found. 

Only  here  and  there  are  any  of  the  hair  follicles  surrounded  by,  or  have 
in  their  neighbourhood  sebaceous  gland  elements. 


ROLE    PLAYED    BY    EPITHELIAL    CELL.  517 

Around  each  hair  folhcle  is  well  organised  connective  tissue,  arranged  circularly, 
and  consisting  of  spindle  cells  with  well  stained  elongated  nuclei. 

The  vessels  running  in  this  connective  tissue  are  dilated,  and  the  walls  are 
thickened. 

Also  surrounding  the  hair  follicles,  especially  marked  at  the  base  and  sides, 
is  a  dense  cellular  infiltration.  This  cellidar  infiltration  consists  largely  of  plasma 
cells  and  small  round  cells. 

The  marked  feature  of  this  cellular  infiltration  is  the  abundance  of  mast  cells, 
many  of  which,  as  usual,  stain  red  with  polychrome  methylene  blue,  but  the  proto- 
plasma  is  homogeneous,  mucinous  in  appearance,  non-granular,  a  type  of  mast  cell 
which  Unna  described  in  Molluscum  fibrosum. 

In  the  centre  of  the  tumour  is  a  large  horny  cyst,  surrounded  by  epithelium 
which  branches  in  a  few  places. 

Towards  the  centre  of  these  branches  the  cells  become  larger,  stain  less  dis- 
tinctly, and  the  spongioplasm  becomes  divided  up  into  loculi — in  short,  the  cell 
becomes  a  sebaceous  gland  cell. 

The  transformation  is  not  quite  complete,  since  there  is  ncit  that  well  marked 
differentiation  of  the  cells,  and  the  clear,  well  stained  nucleus  and  network-like 
protoplasm,  which  is  to  be  seen  in  normal  secreting  sebaceous  gland  tissue. 

These  cells  obviously  are  embryonic  and  functionless. 

In  other  places,  scarcely  any  transition  can  be  made  out ;  the  epithelial  cells 
have  simply  become  swollen,  refuse  the  stain,  have  lost  their  nuclei,  and  are 
degenerated  cells. 

The  collagenous  bundles  are  broken  up,  and  are  not  found  in  the  new  growth. 

The  elastic  tissue  has  in  part  disappeared,  and  nowhere  shows  its  fine  fibrillary 
character  ;  instead,  it  is  broken  up  and  occurs  in  clumps  or  masses. 

In  no  part  of  this  section  are  there  any  traces  of  either  sweat  glands  or  sweat 
ducts. 

One  of  the  cysts  in  the  section  shows  an  intra-cystic  epithelial  growth.  In 
this  cyst  there  is  no  lanugo  hair,  and  no  horny  material  ;  the  cells  of  the  wall  are 
not  so  well  differentiated  as  those  elsewhere,  the  cellular  infiltration  around  is  very 
much  more  marked,  and  no  doubt  the  cells  constituting  this  cyst  are  of  an  earlier 
date  than  the  rest. 

Case  81. — Syringoma. — A  girl,  aged  12  years,  came  up  to  hospital,  complaining 
of  some  spots  on  her  chest.  According  to  the  mother's  history,  the  spots  appeared 
when  the  child  was  one  year  old.     No  other  member  of  the  family  was  affected. 

The  lesions  were  very  faint  yellowish  white,  raised  above  the  surface  of  the 
skin,  and  varied  in  size  from  that  of  a  pin's  head  to  that  of  a  lentil.    The  lesions  were 


518  BIOLOGY   OF   INFLAMMATION    AND    MALIGNANT   DISEASE. 

smooth  on  the  surface  and  embedded  in  the  corium,  so  that  the  skin  was  not  mov- 
able over  them ;  they  were  sharply  circumscribed,  although  the  bigger  ones  were 
not  invariably  regular  in  outline.  The  lesions  gave  rise  to  no  subjective  symptoms. 
The  area  most  affected  was  the  chest,  over  the  sternum  and  beneath  the  clavicles, 
and  in  these  situations  the  largest  lesions  were  to  be  found.  The  neck  was  also 
involved,  lower  eyelid  on  left  side,  lateral  walls  of  thorax  and  abdomen,  and  inner 
sides  of  thighs. 

Histology  (Plates  47  (1,  2)  and  48). — The  epidermis  over  the  new  growth,  which 
is  situated  in  the  upper  portion  of  the  corium,  is  tmaltered.  The  corium  itself  is 
unchanged,  except  for  the  presence  of  the  epithelial  elements,  from  which  the  new 
growth  arises,  and  also  for  a  slight  increase  in  the  fixed  connective-tissue  cells. 

The  new  growth  consists  of  the  following  structures  : — 

(1)  Solid  cords  and  nests  of  epithelial  cells. 

(2)  Cords  and  nests  of  epithelial  cells  which  are  hollowed  out  in  the  centre,  the 
walls  of  the  former  being  made  up  of  two  layers  of  epithelial  cells,  the  walls  of 
latter  of  several  layers,  with  the  central  cells  degenerated  and  staining  badly.  The 
hollow  cords  resemble  in  every  way  the  normal  sweat  ducts. 

(3)  Small  cystic  spaces  with  a  colloid  content.  The  walls  are  made  up  of  one 
or  two  layers  of  epithelial  cells ;  in  parts,  the  cells  are  indistinct,  and  the  nuclei, 
when  present,  are  elongated.  The  colloid  material  is  most  marked  in  those 
cells  in  the  walls  which  have  degenerated,  and  appears  to  be  a  degeneration 
product  of  those  cells. 

Although  the  case  just  mentioned  is  one  in  which  the  lesions  are  widely  dis- 
tributed over  the  body,  the  lesions  on  the  left  lower  eyelid  are  identical  with  those 
seen  so  commonly  only  in  these  situations,  which  cannot  be  distinguished  from 
a  trichoepithelioma  or  from  a  sebaceous  adenoma,  imtil  a  biopsy  has  been  made. 
This  is  the  condition  first  described  and  christened  by  Kaposi^^  and  Biesiadecki^® 
as  Lymphangioma  tuberosum  multiplex,  a  name  which  should  no  longer  appear 
in  any  textbook,  as  the  lesion  is  a  sweat  gland  tumour,  and  has  nothing  to  do  with 
the  lymphatics.  The  few  cases  described  of  hyaline  degeneration  of  the  skin — 
a  painting  of  a  case  with  a  microscopic  section  is  to  be  seen  in  Morgan  Dockrell's^^ 
atlas — are  nothing  more  or  less  than  typical  cases  of  sjTingomata. 

Case  82,  Sebaceous  Adenoma,  was  a  man,  aged  43  years,  who  had  had  flat 
whitish  lesions  in  his  oculo-facial  folds,  as  long  as  he  could  remember.  The  lesions 
were  sharply  circumscribed,  and  about  the  size  of  lentils.  The  only  clinical  difference 
that  I  could  ascertain  between  this  condition  and  those  already  described,  was 
that  each  papule  seemed  to  be  divided  up  into  loculi,  not  unlike  a  wasp's  nest,  and 
the  loculi  were  slightly  more  transparent  than  usual. 


T"f 


1. 

Svi'iiigoina. 


^ 


-#> 


Syriniioiiia,  witli  trii-liocpitliclioinntmis  ■•IrmiMits. 


Plate  47. 


Facing  p.  518. 


/ 


^"-N    . 


'  '°«:-'>  ' 


Syringoma. 


A    ''\    i-<»ll'" 


Plate  48. 


Follows  Phile  47. 


mt 


Follows  Plate  48. 


ROLE    PLAYED    BY    EPITHELIAL   CELL.  519 

Histologically,  the  coriiim  was  filled  with  sebaceous  gland  tissue,  either  fully 
formed,  or,  in  parts,  partly  transformed  from  the  epithelial  cells,  from  which  the 
gland  cells  took  their  origin. 

Case  83. — Mixed  Tumour. — A  woman,  aged  36  years,  had  noticed  some  "  white 
spots  "  beneath  her  lower  eyelids  since  she  reached  the  age  of  puberty.  The  lesions 
were  round,  white,  smooth  on  the  surface,  slightly  raised,  and  clinically  quite  in- 
distinguishable from  any  we  have  already  described. 

A  histological  examination  of  this  mixed  tumour  showed  the  following  points 
(Plate  49). 

In  the  left-hand  part  of  the  section,  beneath  some  lanugo  hair  follicles  (tricho- 
epithelioma), are  some  small  cysts,  below  which  again  are  some  solid  cords  of  epi- 
thelial cells,  both  constituting  a  syringoma. 

The  lanugo  hair  follicles  persist  in  all  parts  of  the  section,  but  in  the  right-hand 
side  is  seen  a  typical  sebaceous  adenoma.  Some  of  the  cells  are  well  formed 
sebaceous  gland  cells,  while  others  have  not  yet  been  formed  from  the  epithelial 
cells  destined  for  the  purjiose. 

Another  type  of  tumour  occurring  in  these  situations,  is  the  EjjitheUoma 
adenoides  cysticum  of  Brooke.  The  lesions  are  more  widely  spread  on  the  face  than 
in  the  cases  just  described,  are  rather  larger,  more  elevated,  and  not  so  flat  on  the 
surface.  The  condition  occurs  in  women,  and  the  lesions  appear  in  childhood.  The 
marked  feature  about  the  disease  is  the  strong  hereditary  element,  mother  and 
daughter  being  usually  affected.  Histologically,  the  lesions  consist  of  masses  of 
epithelial  cells,  which  are  highly  branched  ;  in  the  centre  of  the  masses,  there  may 
be  a  cyst  in  which  lies  a  lanugo  hair,  or  the  cyst  is  filled  wholly  or  in  part  with  some 
homogeneous  substance,  as  is  found  in  a  milium. 

Another  condition  found  also  in  the  same  regions,  the  earlier  lesions  of  which 
are  with  difficulty  to  be  distinguished  from  the  case  just  described,  is  the  Ulcus 
rodens  multiplex. 

This  case  has  been  previously  recorded  by  Dr.  Adamson,^^  ^* : — 

"  '  D —  C — ,  aged  37  years.  History  of  condition  :  Two  and  a-half  years  ago 
he  first  noticed  a  small  red  spot  near  the  outer  canthus  of  the  left  eye,  which 
gradually  grew  in  size.  Seven  months  later  a  second  spot  occurred  near  the  outer 
canthus  of  the  right  eye  and  increased  slowly  in  si^e.  At  about  the  same  time 
another  ulcer  appeared  on  the  forehead  above  the  right  eyebrow.  This  one  has 
healed  of  its  own  accord,  but  has  left  a  scar  exactly  similar  to  the  scarring  which 
has  occurred  round  the  ulcer  underneath  the  eye.  There  is  another  ulcer  on  the 
inner  side  of  his  nose,  and  one  on  the  under  lip  and  another  on  the  side  of  his  neck, 
but  he  cannot  give  any  accurate  account  of  the  dates  at  which  these  appeared. 


520  BIOLOGY   OF  INFLAMMATION    AND    MALIGNANT   DISEASE. 

Present  condition :  In  addition  to  these  six  patches  which  have  been  already 
described,  there  are  numerous  pimples  on  his  face.  They  vary  from  the  size  of  a 
millet  seed  to  that  of  a  split  pea.  As  many  as  twenty  or  thirty  of  these  can  easily 
be  counted.  Were  it  not  for  the  fact  that  he  states  that  the  ulcerated  patches  all 
began  viith.  simple  pimples,  they  would  perhaps  barely  deserve  attention,  as  they 
have  the  appearance  of  small  sebaceous  glands  in  which  the  ducts  are  blocked. 
Two  of  these  pimples  have  been  excised  and  examined  microscopically,  as  well  as 
pieces  from  the  six  ulcerated  patches  above  alluded  to.  They  one  and  all  exhibit 
the  microscopical  appearance  of  typical  rodent  ulcers,  as  are  displayed  under  the 
microscope.  The  patient  is  now  undergoing  electrical  treatment  with  X-rays 
four  times  a  week,  and  is  deriving  considerable  benefit  from  it.  The  ulcers  are 
healing  rapidly.  N.B.  :  The  patient  remained  in  hospital  about  six  weeks  after 
he  was  shown,  during  which  time  the  ulcers  completely  healed  ;  but  the  pimples, 
though  they  improved  and  diminished  in  size,  and  in  some  instances  entirely  dis- 
appeared, had  not  altogether  vanished.  The  patient  declined  to  remain  any 
longer.' 

"  Later  the  patient  was  again  in  the  hospital,  and  many  of  the  lesions  were 
excised  and  others  were  scraped.  In  1907,  by  the  kindness  of  Mr.  Bruce  Clarke, 
I  (Dr.  Adamson)  had  an  opportunity  of  seeing  this  patient.  There  were  then 
altogether  seventeen  lesions  upon  the  face,  varying  in  size  from  small  nodules 
of  the  dimensions  of  a  pin's  head  up  to  ulcerated  lesions  of  1|  in.  in  diameter. 
There  were  also  scars  marking  the  excision  or  scraping  of  former  lesions.  For 
purposes  of  description  the  lesions  then  present  may  be  divided  into  groups  as 
follows : — 

"  (1)  Six  nodules,  reddish  in  colour  and  serai-translucent,  of  the  size  of  a  large 
pin's  head  to  that  of  a  millet  seed,  and  distributed  over  the  left  cheek  and  the  fore- 
head. 

"  (2)  Nodules  of  the  size  of  a  millet  seed  to  that  of  a  split  pea,  dull  red  in 
colour,  raised,  but  flat  on  their  surface,  firm  and  semi-translucent ;  a  grouj)  of  three 
upon  the  right  temple  at  the  outer  angle  of  the  orbit,  two  just  below  the  left  ala  of 
the  nose,  one  on  the  left  upper  eyelid,  and  one  on  the  left  brow. 

"  (3)  Larger  lesions,  which  have  undergone  treatment  on  a  former  occasion  ; 
two  on  the  forehead,  one  on  the  left  ala  of  the  nose.  These  were  from  J  in.  to  |  in. 
in  diameter,  with  a  central  scar  and  a  marginal  rolled  edge. 

"  (-i)  An  irregularly  shaped  lesion,  partly  scarred,  partly  ulcerating,  and 
partly  crusted,  extending  from  the  inner  canthus  of  the  right  eye  on  the  right  cheek, 
here  and  there  showing  a  raised  nodular  edge.  This  lesion  measures  1|  in.  in 
length  by  f  in.  in  diameter. 


ROLE  PLAYED  BY  EPITHELIAL  CELL.  521 

"  (5)  A  similar  iilcer,  1  in.  by  11-  in.,  involving  the  inner  canthus  on  the  left  side, 
the  lower  lid,  and  the  left  cheek. 

"  (6)  About  the  forehead  and  cheeks  there  are  scattered  a  few  niilia,  but  there 
are  none  on  the  lesions  themselves." 

Histology  (from  sections  kindly  given  to  me  by  Mr.  Onslow  Ford). — Beneath 
the  ulcerating  surface,  is  a  new  growth  of  spindle  cells  ;  the  cellular  masses  are 
irregular  in  outline,  and  in  many  places  branch — features  typical  of  a  rodent  ulcer. 

Only  here  and  there  are  cysts  to  be  found  in  the  spindle  celled  masses,  but 
they  are  not  of  the  type  found  in  those  cases  described  by  Jarisch.  Those  present 
in  this  section  are  empty  and,  probably,  spurious.  Around  the  new  growth  is  a 
dense  cellular  infiltration,  consisting  of  polymorphonuclear  leucocytes,  plasma  cells 
and  lymphocytes. 

The  most  interesting  part  of  the  section  is  the  occurrence  of  a  true  sebaceous 
adenoma  in  the  healthy  corium  siuTOunding  the  new  growth,  and  also  masses  of 
epithelial  cells  not  quite  mature,  on  their  way  to  form  sebaceous  gland  tissue.  It 
is  not  uncommon  to  find  a  trichoepithelioma  and  a  sebaceous  adenoma  in  the  same 
section  as  a  rodent  ulcer  {vide  Plate  46),  although  the  simultaneous  occurrence 
has,  as  far  as  I  know,  not  been  described.  The  combined  growth  undoubtedly 
speaks  largely  in  favour  of  a  rodent  ulcer  being  a  neevus,  and  having  its  origin  in 
epithelial  cells  which  are  not  mature  enough  to  form  any  specialised  epithelial 
structure. 

In  these  sections,  and  in  others  from  smiilar  cases,  which  I  have  examined 
since,  I  have  frequently  found  mole  elements,  that  is  to  say,  locaHsed  collections 
of  embryonic  endothelial  cells  in  the  periphery  of  the  epithelioraatous  growth. 

Although  I  have  described  only  one  case  of  each  type,  it  is  only  with  the  idea 
of  giving  the  main  clinical  and  histological  features  thereof,  since,  if  several  cases  be 
microscopically  examined,  although  the  clinical  aspect  of  all  may  be  the  same, 
extraordinary  variations  are  to  be  met  with.  * 

For  instance,  in  the  so-called  Epithelioma  adenoides  cysticum — a  bad  name, 
as  it  gives  no  clue  to  the  adenoid  tissue  affected — one  may  find  lesions  more  closely 
resembling  the  Trichoepithelioma  papulosum,  as  described  in  Case  80,  while,  on  the ' 
other  hand,  the  origin  of  the  epithelial  masses  from  the  lanugo  hair  follicles  may  be 
so  difficult  to  make  out,  because  of  the  more  embryonic  nature  of  the  cells,  that 
the  condition  becomes  more  like  that  seen  in  multiple  rodent  ulcer. 

Take  multiple  rodent  ulcer ;  in  some  cases,  cysts  are  evident,  hence  the  name 
multiple  benign  cystic  epithelioma.  The  walls  of  the  cysts  consist  of  cubical  cells, 
almost  indistinguishable  from  mature  rete  cells,  so  that  the  epithelial  masses  in 
which  the  cysts  occur  suggest  an  origin  from  the  lanugo  hair  follicles.     In  other 


522  BIOLOGY    OF   INFLAMMATION   AND   MALIGNANT   DISEASE. 

cases,  again,  the  epithelial  masses  consist  of  spindle  cells  only,  and  a  diagnosis  could 
not  be  made  from  an  ordinary  rodent  ulcer. 

See  again  how  the  common  single  rodent  ulcer  itself  varies.  Some  consist  of 
pure  spindle  cells,  while  in  others  cubical  cells  are  found,  with  horny  matter  in  the 
centre. 

These  variations  are  links  in  one  pathological  chain,  and  entirely  depend  upon 
the  time  the  cells  forming  the  tumour  were  laid  down  in  their  embryonic  life. 

The  most  mature  are  the  true  adenomata,  %az.,  trichoepithelioma,  sebaceous 
adenoma,  and  syringoma.  Going  back,  we  meet  with  a  condition  which  can  be  said 
to  arise  from  lanugo  hair  follicles — a  trichoepithelioma,  but  at  a  period  when 
sebaceous  gland  and  sweat  gland  tissue  has  not  been  organised,  as  seen  in  Brooke's 
type,  which  would  be  better  called  Trichoepitkelmna  jiapidosum  (Brooke).  Still 
further  receding,  we  reach  the  condition  when  the  origin  of  the  epithelial  masses 
from  the  lanugo  hair  follicles  is  by  no  means  clear,  although  suggested.  As  the 
lesioias  in  which  this  condition  is  found  histologically,  ulcerate  clinically,  they  should 
be  called  Trichoepithelioma  papulosum  ulcerans. 

Lastly,  in  those  cases  in  which  the  cells  are  too  embryonic,  when  the  epithelial 
masses  are  formed  from  the  primary  epithelial  cells,  before  hair  folhcles  are  even 
conceived,  the  term  Ulcus  rodeiis,  be  they  single  or  multiple,  should  stand. 

If  we  regard  rodent  ulcer  as  a  malignant  disease,  and  this  is  quite  logical,  although 
it  does  not  form  metastases,  the  reader  will  at  once  observe  that  there  are  two 
kinds  of  mahgnancy — one  which  affects  embryonic  cells,  the  other  which  affects 
mature  cells. 

Embryonic-cell  malignancy,  as  far  as  the  epithelium  is  concerned,  differs  from 
the  mature-cell  malignancy  in  several  ways.  The  cells  are  more  closely  packed 
together,  ail  the  cells  are  the  same,  i.e.,  there  is  no  nuclear  or  nucleolar  activity 
to  make  them  differ  from  one  another  morphologically.  The  gix)wth  is  more 
regular ;  there  is  not  so  much  tissue  invasion,  the  protective  leucocytic  infiltration 
is  less  marked — indeed  it  may  be  almost  entirely  absent ;  it  does  not  form  meta- 
stases, or  give  rise  to  lymphatic  gland  enlargement ;  and,  lastly,  the  malignancy 
is  less  pronounced.  The  tumour  is  malignant  in  the  sense  that,  if  allowed  to  do 
so,  it  will  extend  and  eat  through  any  tissue  that  bars  its  progress.  As  the  term 
malignancy,  used  in  this  sense,  is  apt  to  be  confounded  with  the  usual  meaning  of 
the  ^^'ord,  I  cannot  help  thinking  that  it  would  be  better  to  designate  the  malignancy 
of  embryonic  cells  as  simply  "'  embryonic  activity,"  and  to  use  the  term  "  mahgnant," 
when  matitre  cells  behave  pseudo-parasitically,  or  exhibit  the  nuclear  and  nucleolar 
activity,  which  I  have  just  described. 

WTiat  is  the  reason  for  the  frequency  of  these  growths  in  the  orbito-facial 


ROLE   PLAYED    BY   EPITHELIAL   CELL.  523 

and  naso-facial  grooves  ?  Generally  speaking,  cutaneous  new  growths,  which  are 
usually  of  epithelial  origin,  are  more  common  in  raan  than  in  tlie  rest  of  the 
mammalia,  and  new  growths  are  more  hkely  to  occur  in  situations  which  once  served 
a  purpose.  Most  mammals  have  speciaHsed  hairs  in  the  orbito-facial  fold,  corre- 
sponding to  the  supra-orbital  eyebrows,  and  no  doubt  serving  the  same  purpose ; 
further  important  glands  occur  in  both  the  orbito-facial  and  naso-facial  folds  of 
many  animals. 

Owing  to  a  more  or  less  uniform  distribution  of  sebaceous  and  sweat  glands, 
man  stands  in  no  need  of  those  facial  glands,  so  characteristic  of  many  antelopes. 

The  commonest  epithelial  growth  is  in  connection  with  the  lanugo  hair  follicles 
— trichoepithelioma — growths  which  are  usually  limited  to  the  face,  and  which, 
in  my  opinion,  arise  in  those  lanugo  hair  follicles  which  are  atavistic  of  the  lower 
eyebrows.  Lanugo  hair  is  embryonic,  is  atavistic,  and  a  remnant  of  the  complete 
body  hair-covering,  whicli  is  typical  of  most  of  the  mammals. 

The  adult  members  of  the  orders  Sirenia  and  Cetacea  are  hairless,  but  the 
young  of  the  former  are  covered  with  hair,  and  in  the  young  of  the  latter,  the  hair 
IS  Hrnited  to  the  face.  Tlie  only  exceptions  are  the  Beluga  or  White  Whale,  and  the 
Monodon  or  Narwhal.  Young  elephants  have  lanugo  hair,  like  the  liuman  hair; 
The  lanugo  hair  folhcles  soon  disappear,  but  some  on  the  face  remain,  and  they 
are  those  which  are  atavistic  of  the  specialised  hairs,  which  ought  to  have  formed 
the  lower  eyebrows. 

Syringoma  is,  again,  a  common  new  growth. 

In  man,  the  sweat  glands  are  uniformly  distributed  over  the  body,  but  in  many 
animals  they  are  localised — for  instance,  to  the  soles  of  the  feet  in  some  of  the 
rodentia — or  they  may  be  completely  absent,  as  in  the  Sirenia  and  Cetacea. 

In  animals,  most  of  the  sweat  glands  open  into  the  hair  follicles,  but  some  have 
their  own  point  of  exit  in  the  epidermis,  the  latter  being  the  case  in  adult  life  only. 

As  in  man,  the  sebaceous  glands  in  animals  are  usually  associated  with  the 
hair  follicles,  but  may  be  found  alone,  viz.,  peri-anal  glands,  etc.,  but  these  are 
probably  specialised  glands. 

So  closely  are  the  sebaceous  glands  connected  with  the  hair  follicles,  that  when 
the  hair  of  the  Cetacea  disappears,  the  sebaceous  glands  vanish  also. 

Like  the  sweat  glands,  the  sebaceous  glands  are  in  some  animals  localised,  for 
instance,  to  the  snout  and  anus  in  the  Manis  or  long-tailed  Pangolin,  or  they 
may  be  absent  altogether,  although  the  animal  be  well  covered  with  hair,  viz., 
Cholcepus  and  Chrysochloris. 

With  the  possible  exception  of  the  peri-anal  glands,  man  possesses  no  specialised 
skin  glands,  which  are  so  characteristic  in  other  mammals,  and  which  are  made 


524  BIOLOGY    OF   INFLAMMATION   AND    MALIGNANT   DISEASE. 

up  of  either  sweat  or  sebaceous  glands,  or  of  a  mixture  of  the  two.  They  are 
situated  in  different  parts  of  the  body,  in  the  various  orders,  the  face  glands  being 
t^-pical  of  the  Artiodactyla  and  so  on. 

Of  the  face  glands  there  are  two  kinds  : — • 

(a)  Supra-orbital,  as  in  the  Beisa  {Oryx  heisa). 

(b)  Sub-orbital  or  ante-orbital. 

The  second  group  is  typical  of  certain  deer,  and,  in  most  cases,  is  designated  by  a 
fold  of  skin  or  pocket,  the  edges  of  which  are  sometimes  inverted ;  these  are  the 
so-called  tear  grooves — folUculi  lacrymales. 

In  my  opinion,  the  small  tumours  so  frequent  below  the  lower  eyelid,  which 
may  be  made  up  of  lanugo  hair  follicles,  and  often  of  sebaceous  and  sweat  gland 
tissue,  are  reversions  to  the  face  glands  of  deer. 

The  tumours  are  often  mixed,  which  is  another  point  in  favour,  since  the  ante- 
orbital  gland  of  the  Gnu  is  made  up  of  both  sebaceous  and  sweat  glands,  which 
may  open  separately  in  the  epidermis,  or  direct  into  the  hair  follicles. 

If  the  sebaceous  gland  type  of  tumour  be  carefully  examined,  it  is  often  found 
with  remains  of  a  lanugo  hair  follicle  in  the  centre.  Human  beings  are  not  only 
those  affected  with  epithelial  growths  below  the  lower  eyelid ;  I  have  seen  the 
same  in  monkeys.  For  my  animal  material  I  am  indebted  to  Dr.  Plimmer, 
pathologist  to  the  Zoological  Society. 

Summary. 

Tumours  affecting  the  orbito-facial  and  naso-facial  grooves  are  of  epithelial 
origin,  and  atavistic  of  both  the  lower  eyebrows  and  the  specialised  glands 
found  in  these  regions  in  many  of  the  mammalia.  There  is  probably  not  an 
individual  which  will  not  show  some  trace  of  epithelial  embryonic  tissue  (naevus), 
when  a  section  is  made  from  the  skin  of  these  grooves. 

All  the  tumours,  from  a  simple  lanugo  hair  follicle  growth,  to  a  rodent  ulcer, 
are  links  in  one  chain,  the  former  being  the  head  or  most  mature,  the  latter  the  tail 
or  most  embryonic.  As  they  are  all  links,  the  histological  difEerences  of  one  clinical 
entity  is  at  once  explained. 

There  are  two  kinds  of  malignancy.  One  which  is  better  called  embryonic 
activit)',  of  which  an  example  is.  the  rodent  ulcer.  The  more  embryonic  tissue  is, 
the  greater  its  activity,  and  hence  the  less  benign  it  is. 

The  other  form  of  malignancy  is  the  true  malignancy,  i.e.,  the  condition  which 
gives  rise  to  lymphatic  gland  enlargement  and  metastases.  It  is  due  to  nuclear 
and  nucleolar  activity  of  the  mature  cells.     True  malignancy  can  probably  be 


ROLE  PLAYED  BY  EPITHELIAL  CELL.  525 

produced  by  many  causes,  all  of  which  are  irritative.  It  is  also  probable  that  true 
malignancy  is  really  a  localised  effort  on  the  part  of  the  host  to  combat  the  irritation 
which  commenced  the  process.  The  more  pressing  the  stimulus,  the  greater  the 
response,  until  the  host's  cells  themselves  become  parasitic  upon  the  host. 

1  McDonagh  (1912),  "  Brit.  Journ.  of  Derm.,"  xxiv,  291. 

-  McDonagh  (1914),  "  Journ.  of  Cutan.  Dis.,"  xxxii,  11. 

'  McDonagh  (1914),  '•  Arcliiv   f.  Derm.  u.  Syph.,"  cxx,  289. 

*  Urma  (1905),  "  Zcitschrf.  f.  Krebsforschung,"  iii,  218. 

^  V.  Recklinghausen  (1894),  "  Monatsh.  f.  Prak.  Dermat.,"  xix,  595. 

"  McDonagh  and  Wallis  (1913),  "  Bioch.  Journ.,"  vii,  517. 

'  Unna  (1913),  "  Biochem.  der  Haut."     G.  Fischer.     Jena. 

»  Russell  (1890),  "  Brit.  Med.  Journ.,"  ii,  1297. 

»  Plimmer  (1899),  "Practitioner,"  Ixii,  453. 

'"  Apolant  u.  Embden  (1905)  "  Zeitsohrf.  f.  Krebsforschung,"  iii,  579. 

"  Wallis  and  Soholberg  (1910),  "  Quart.  Journ.  of  Med.,"  iii,  301. 

'-  Ibid.  (1911),  iv,  153. 

"  Adamson  (1908),  "Lancet,"  ii,  1133. 

"  Bruce  Clark  (1903),  "Transact,  of  Clin.  Soc,"  xx-xvi,  271. 

'^  Kaposi  (1899),  "  Handatlas  der  Hautkrankheiten."    Wien. 

'"  Biesiadecki  (1892),  "  Untersuch.  aus  dem  path.  Instit.  zu  Krakau." 

"  Morgan  Dookrell  (1905),  "  An  Atlas  of  Dermatology."     Longmans,  Green  &  Co.  London. 

'8  McDonagh  (1915),  "Brit.  Journ.  of  Derm.,"  xxvii,  91. 

WORKS  CONSULTED. 

Max  Weber  (1904),  "  Die  Saugetiere."     G.  Fischer.     Jena. 

Brinkmann  (1911),  "  Bidrag  til  Kundskaben  cm  Drovtyggernes."     Kobenhavn, 


CHAPTER  XLVI. 

THE  ROLE  PLAYED  BY  A  LYiffHOCYTE  IN  INFLAMIVIATION,  .iND  ITS 
PROBABI-E  EEL4TI0NSHIP  TO  SARCOMA. 

Introduction. 

The  first  consideration  will  be  given  to  the  life  history  of  the  lymphocyte, 
including  its  origin,  and  the  cell  to  which  it  gives  rise. 

The  biology  and  biochemistry  of  the  plasma  cell  will  be  discussed,  then  the 
role  which  the  lymphocytes  and  plasma  cells  play  in  acute  and  chronic  inflammation, 
and,  finally,  the  probable  relationship  which  exists  between  the  latter  and  sarcoma 
will  be  dealt  with. 

Origin  of  Lymphocytes. 

Lymphocytes  have  their  origin  in  the  granoplasm  of  endothelial  cells  (Plate  21 
(1,  2)),  and  they  are  formed  mosb  abundantly  in  the  spleen  and  in  the  lymphatic 
glands.  They  may  also  be  formed  in  the  bone-marrow,  and  in  any  tissue  where 
their  presence  is  required. 

It  is  owing  to  their  capacity  for  being  formed  in  the  skin,  that  a  few  observers 
have  stated  that  the  corium  is  studded  with  minute  lymphatic  gland  elements, 
which,  of  course,  is  not  the  case,  strictly  speaking. 

It  is  generally  held  that  lymphocytes  are  formed  only  in  the  lymphatic  glands, 
spleen,  and  bone-marrow,  and  that  if  they  are  required  at  a  certain  spot,  in  the  skin 
for  instance,  that  a  message  is  conveyed  to  the  nearest  lymphatic  glands  to  elaborate 
lymphocytes  which,  when  formed,  travel  the  round  of  the  systemic  blood  stream, 
before  arriving  at  the  station  from  which  the  call  came. 

What  the  nature  of  the  message  is,  how  it  travels  along  the  different  lymphatics, 
and  how  the  lymphocytes  enter  the  circulation,  are  points  which  are  not  explained. 

It  would  not  be  nearly  so  hypothetical  to  assume  that  lymphocytes  are  formed 
in  situ,  that  the  lymphatic  vessels  are  capable  of  forming  more  if  required,  and 
that  the  lymphatic  glands  are  of  the  nature  of  a  base,  wherein  an  almost  inexhaustible 
supply  can  be  produced.     In  order  to  see  what  really  happened,  I  removed  chancres 


ROLE    PLAYED    BY   LYMPHOCYTE.  527 

in  all  stages,  with  a  long  strip  of  skin  posterior  to  them,  which  is  a  simple  matter 
when  the  sores  are  situated  on  the  tip  of  a  long  foreskin.  If  the  patient  is  circum- 
cised, transverse  sections  may  be  obtained  of  the  base,  and  an  examination, 
therefore,  will  give  the  clue  as  to  what  is  happening  between  the  sore  and  the 
nearest  chain  of  lymphatic  glands. 

So  far  as  the  l3nnphatic  system  is  concerned,  one  finds  a  dilatation  of  the 
vessels  with  a  proliferation  of  the  endothelial  cells,  surrounded  by  a  collection  of 
mixed,  small  round  cells  (lymphocytes)  and  plasma  cells.  Here  and  there,  an 
enormous  collection  of  cells  is  to  be  seen,  in  the  area  covering  the  whole  field  of  the 
microscope.  In  the  centre,  instead  of  finding  a  gaping  lymphatic  vessel,  a  collection 
of  endothelial  cells  is  to  be  seen,  some  of  which  have  become  fused  together  to  form 
a  giant  cell,  while  the  protoplasm  of  others  is  in  the  process  of  giving  rise  to  lympho- 
cytes, as  in  Plate  21  (1,  2).  Outside  this  endothelial  collection,  are  to  be  seen 
numerous  large  mononuclear  leucocytes  and  plasma  cells.  Seeing  such  a  field 
under  the  microscope,  and  being  unaware  what  the  tissue  was,  one  would  imme- 
diately say  that  it  was  a  section  from  a  lymphatic  gland. 

The  endothelial  proliferation  is  in  some  places  so  marked,  that  the  lymphatic 
vessel  becomes  obliterated ;  hence  the  nature  of  the  lymphangitis  or  lymphatic 
cords  that  are  so  commonly  to  be  felt  running  between  the  sore  and  the  glands. 
In  some  cases,  as  serial  sections  show,  the  cellular  infiltration  is  more  marked  in 
some  areas  than  in  others,  hence  the  explanation  of  the  nodular  character  that  the 
lymphangitis  or  lymphatic  chain  of  beads  sometimes  takes. 

From  what  has  been  mentioned,  there  is  now  proof  that  lymphocytes  may 
be  formed  from  the  endothelial  cells  of  the  lymphatics.  From  repeated  examina- 
tions, I  cannot  help  coming  to  the  conclusion,  that  the  giant  cells  which  are  to  be 
met  with  in  chronic  inflammation  are  nothing  more  nor  less  than  a  fusion  of  endo- 
thelial cells  which  block  the  lymphatic,  of  the  nature  of  an  endolymphangitis, 
a.nalogous  to  an  endophlebitis  or  endarteritis.  The  fact  of  the  nuclei  collecting 
together  at  one  pole  of  a  giant  cell,  as  they  not  infrequently  do,  does  not  argue 
against  the  correctness  of  the  above  theory,  since  endothelial  proliferation  ma}^ 
take  place  in  one  area,  and  not  around  the  whole  circumference  of  a  vessel,  as  is 
again  witnessed  in  veins  and  arteries. 

In  a  chancre,  local  lymphangitis  is  well  marked,  and  typical  endothelial  cells 
with  embryo  hanphocytes  in  their  protoplasm  are  also  to  be  seen,  before  the 
lymphatic  vessels  posterior  to  the  sore  show  a  similar  change,  so  it  follows  that 
lymphocytes  can  be  formed  in  the  site  of  the  infection. 

In  the  lymphatic  glp,nds,  lymphocytic  formation  is  at  its  zenith,  and,  at  first 
sight,  it  appears  difficult  to  say  whether  the  lymphocytes  so  formed  are  destined 

2l 


528  BIOLOGY   OF   INFLAMMATION   AND    MALIGNANT   DISEASE. 

to  remain  therein  to  do  their  work  in  hco,  or  whether  they  are  sent  out  to  the 
site  of  infection.  On  further  examination,  it  is  clear  that  many,  if  not  the  majority, 
of  the  lymphocytes  formed  in  a  lymphatic  gland,  remain  to  act  where  they  are 
formed,  for  the  following  reasons  :  In  early  generahsed  syphihs,  there  is  a  marked 
lymphocytosis,  which  is  more  pronounced  in  the  severe  than  in  the  light  cases,  and 
which  is  increased  by  treatment  ^^.  The  greatest  enlargement  of  the  lymphatic 
glands  is  not  in  the  severe  cases,  and,  moreover,  there  exists  no  ratio  between  the 
degree  of  lymphoc\i;osis  and  the  enlargement  of  the  lymphatic  glands.  On  the 
contrarj^,  the  greatest  lymphocjiiosis  is  most  marked  in  those  cases  in  which  the 
glands  are  only  shghtly  enlarged.  In  Hodgkin's  disease,  the  glandular  enlargement 
may  be  enormous,  but  there  is  no  lymphocytosis.  Furthermore,  if  the  bone-marrow 
is  examined  post-mortem,  in  every  case  which  has  succumbed  to  a  lymphocytoraa, 
it  will  be  found  to  be  diseased  only  in  those  cases,  in  which,  during  Hfe,  the  patient 
had  a  lymphocytosis,  or  in  other  words,  it  gives  the  blood  picture  of  a  lymphatic 
leucaemia.  Hence  the  probability  is,  that  all  the  lymphocytes  which  circulate 
in  the  blood  stream,  are  of  bone-marrow  orisin. 


Staining  Characters  of  Lymphocytes. 

An  endothelial  cell  containing  embryo  lymphocj-tes,  when  examined  in  vivo 
stained  with  borax  methylene  blue,  appears  to  be  full  of  numerous  small  round 
cells.  ^Vhen  examined  in  fixed  specimens  (Plate  21  (1,  2)),  the  cells  in  process  of 
formation  are  found  scattered  about  in  the  protoplasm,  and  frequently  appear  to 
be  divided  into  groups  by  septa.  The  endothelial  cell  degenerates  after  the 
lymphocjiies  have  left  it. 

The  embryo  lymphooiies  stain  deeply  with  haematoxyhn  and  basic  dyes 
and  in  sections  stained  ^vith  Pappenheim's  mixture  of  pjTonin  and  methyl  green, 
some  stain  a  brilhant  red,  and  some  a  brilhant  green.  Chemically,  they  consist 
of  nucleo-protein  and  a  hpoid-globulin  adsorption  compound.  It  is  the  prevalence 
of  one  substance  over  the  other,  which  determines  as  to  whether  they  will  stain 
with  the  pyronin  or  the  methyl  green,  the  latter  being  practically  specific  for 
nuclein,  and  the  former  for  lipoid-globulin. 

The  stained  masses  are  distributed  unevenly  in  the  cell,  but  in  nearly  every 
case  they  cover  practically  the  whole  cell,  hence  the  reason  why  a  lymphocyte  looks 
as  if  it  is  all  nucleus. 

It  is  not  until  the  cells  become  adult,  that  the  nucleo-protein  becomes  differen- 
tiated into  chromatin  threads  and  dots,   then  the   lipoid-globulin   becomes   the 


ROLE   PLAYED    BY   LYMPHOCYTE.  529 

colloidal  membrane  of  the  nucleolus — the  vital  part  of  the  nucleus.      When  this  is 
complete  we  have  the  small  lymphocyte. 

Function  of  a  Lymphocyte. 

Now  what  is  the  function  of  the  small  h'mphocyte  ?  One  answer  can  be  given 
with  certainty,  and  that  is,  that  it  is  '"  not "  phagocytic  ;  its  function  is  doubtless  a 
chemical  one,  of  the  nature  of  a  ferment  action,  an  action  which  is  probably  more 
marked  in  the  cell  to  which  it  gives  rise  than  in  its  own  self. 

If  sections  are  stained  with  rongaht  white,  nuclei  stain  blue,  which  proves 
that  they  contain  free  oxygen^.  If  sections  are  treated  with  benzidine  and 
hydrogen  peroxide,  the  nuclei  also  stain  blue,  which  proves  the  presence  of  a 
peroxydase.  Therefore,  nuclei  contain  free  oxygen  and  a  ferment  for  activating 
the  same,  and  the  action  of  the  latter  is  doubtless  accelerated  by  the  iron,  as  in  the 
ease  of  the  red  blood  corpuscles.  The  oxidising  action  of  a  lymphocyte  may  be 
used  directly  against  the  cause  for  which  the  cell  is  elaborated  ;  or  indirectly,  by 
gi\'ing  up  the  oxygen  to  the  protoplasm  of  the  cell  to  which  it  gives  rise. 

The  Cell  which  Develops  from  Lymphocytes. 

This  now  brings  me  to  describe  the  cell  which  develops  from  the  small  mono- 
nuclear leucocyte,  viz.,  the  plasma  cell. 

Plasma  cell. — The  general  opinion  prevails  that  a  plasma  cell  originates  from  a 
lymphocyte,  but  there  are  still  a  few  observers  who  hold  the  view  that  a  connective 
tissue  cell  is  its  progenitor. 

Connective-tissue  cells  are  in  a  way  insignificant  cells,  as  their  function  in 
inflammation  is  mainly  mechanical ;  they  act  as  a  barrier,  which  is  still  further 
strengthened  by  multiple  division  of  the  parent  cells  into  young  connective-tissue 
cells.  Collagen  and  elastin  result  from  the  old  connective-tissue  cells,  and  the 
disappearance  of  the  former,  with  first  clumping,  and  then  disappearance  of  the 
latter,  which  is  frequently  referred  to  by  skin  histologists  as  being  diagnostic  of 
certain  affections,  is  what  always  takes  place  when  there  are  sufficient  inflammatory 
cells  present. 

Connective-tissue  cells,  hke  other  cells,  degenerate  ;  hence  ib  might  be  expected 
that  certain  chemical  entities  are  to  be  met  with,  in  the  degenerated  products.  The 
name  collagen  is  given  to  one  form  of  degeneration  of  a  connective-tissue  cell,  and 
it  is  a  substance  which  is  recognised  by  the  affinity  it  has  for  acid  stains  such  as 
acid  fuchsin  and  water  blue.     This  acidophilia  is  due  to   the  presence  of    basic 

2l2 


530  BIOLOGY   OF   INFLAMMATION   AND    MALIGNANT   DISEASE. 

amino-acids.  iiame]}%  arginine,  lysine  and  histidine,  as  Unna  ^  has  ingeniously 
uhown. 

As  stated  in  Chapter  XLV.,  degenerations  such  as  colloid,  hyaline,  etc.,  are  true 
T?liemical  substances,  or,  in  other  words,  analytic  products  of  protein  metabolism. 
In  some  degenerations,  certain  amino-acids  are  more  active  than  in  others,  some 
amino-acids  act  as  acids,  others  as  bases,  some  have  a  strong  reducing  action,  others 
have  none ;  hence  it  is  at  once  obvious  why  the  different  forms  of  degenerations 
have  not  got  identical  staining  properties.  Elastin  is,  doubtless,  likewise  a 
degeneration  product  of  connective-tissue  cells,  and  the  way  in  which  it  differs 
from  collagen  is  entirely  dependent  upon  the  predominating  amino-acids.  Elastin 
is  basophilic,  owing  to  the  excess  of  glycocoll,  leucine,  alanine  and  phenylalanine 
over  the  other  amino-acids^ ;  moreover,  reducing  amino-acids  are  found  in  elastin, 
namely,  leucine  and  tyrosine,  therefore  it  is  clear  why  the  staining  properties  of 
these  two  degeneration  products  should  be  so  different. 

By  an  increase  in  the  size  of  the  protoplasm  of  a  lymphocyte,  a  plasma  cell 
is  formed  ;  the  protoplasm  bulges  in  one  diameter  more  than  in  another,  so  that 
the  cell  has  a  "  cottage  loaf "  appearance,  or  in  other  words,  the  nucleus  looks  as 
if  it  was  excentrically  placed. 

The  nucleus  of  a  plasma  cell  does  not  differ  from  that  of  a  lymphocyte  ;  it  is 
di%'ided  up  into  chromatin  masses  and  threads,  in  the  centre  of  which  a  nucleolus 
is  generally  to  be  seen.  It  is  in  the  protoplasm  that  the  chief  difference  lies,  for, 
in  fixed  specimens,  a  small  lymphocyte  appears  to  have  no  protoplasm,  while  a  plasma 
cell  has  about  three  times  as  much  as  the  nucleus,  and  it  stains  brilliantly  with 
pyronin. 

If  the  cells  are  examined  in  vivo,  stained  with  borax  methylene  blue,  the 
distinction  is  less  evident,  as  the  nucleus  of  the  plasma  cell  is  more  centrally  placed, 
and,  if  one  depends  upon  the  amount  of  protoplasm  surrounding  the  nucleus  to 
draw  the  distinction,  one  is  at  once  confronted  with  the  similarity  of  a  plasma  cell 
to  a  large  mononuclear.  In  many  cases,  it  is  extremely  difficult  to  differentiate 
between  the  two  cells,  the  plasma  cell  and  the  large  lymphoc^iie  ;  but  the  following 
four  points  will  materially  assist  one  in  the  task  : — 

(1)  One  pole  of  the  nucleus  generally  touches  the  circumference  of  the  proto- 
plasm in  one  place,  in  a  plasma  cell. 

(2)  In  the  protoplasm  of  a  plasma  cell,  irregular  masses  are  to  be  seen,  and 
they  stain  deeply  with  the  methylene  violet  moiety  of  the  borax  methylene  blue. 

(.3)  The  nucleus  of  a  plasma  cell  stains  more  deeply. 

(4)  The  nucleus  of  the  large  mononuclear  usually  contains  more  than  one 
nucleolus. 


ROLE   PLAYED    BY    LYMPHOCYTE.  531 

The  deep  blue  staining,  taken  on  by  these  masses  which  are  to  be  seen  in  the 
protoplasm,  is  copied  by  the  nucleolus,  therefore  the  two  structures  have  one  point 
in  common.  Since  the  methylene  violet  is  the  basic  half  of  the  borax  methylene 
blue,  it  may  be  assumed  that  both  the  masses  and  the  nucleolus  prefer  basic  stains. 
Further  than  this,  staining  in  vivo  will  not  take  us.  If  we  now  turn  our  attention 
to  fixed  specimens,  and  «tain  them  with  Pappenheim's  stain,  we  inuuediately  notice 
that  the  protoplasm  of  the  plasma  cell  stains  homogeneously  with  pyronin,  that  it 
is  not  divided  up  into  masses,  and  that  the  nucleolus  also  stains  a  brilliant  red. 

If  sections  are  left  for  some  hours  in  weak  solutions  of  various  reagents,  and 
then  stained  with  Pappenheim's  stain,  it  is  found  that  the  protoplasma  of  the  plasma 
cells  and  the  nucleolus  are  far  more  resistant  than  the  protoplasm  of  other  cells, 
and  that  they  behave  hke  a  globulin.  Owing  to  the  optical  activity  of  both  the 
nucleolus  and  the  protoplasm,  the  globulin  is  shown  to  be  in  a  colloidal  adsorption 
compound  with  a  lipoid.^ 

All  cells  contain  lipoids,  and  observers  who  have  paid  attention  to  the  chemistry 
of  cells,  have  always  been  careful  to  treat  their  material  first  with  alcohol  and  ether, 
so  as  to  remove  the  lipoids.  No  one  has  hitherto  recognised  that  all  the  lipoids 
cannot  be  extracted  by  alcohol  and  ether;  in  fact,  those  which  are  in  an  adsorption 
compound  with  globulin  are  untouched.  These  lipoid-globuhn  adsorption  com- 
pounds are  the  very  essence  of  the  existence  of  the  cells,  indeed  of  life  itself.  I 
need  only  mention  that  the  granules  of  the  choroid  plexus,  and  NissFs  granules 
are  made  up  of  lipoid-globulin  complexes,*  to  substantiate  my  statement. 

Hitherto,  the  most  resistant  part  of  the  protoplasm  has  been  looked  upon  as 
being  a  nucleo-protein,  and  to-day  it  is  generally  held  that  Nissl's  granules  are  of 
the  same  nature.  The  name  "  plastein  "  has  frequently  been  given  to  this  resistant 
substance,  and  to  several  other  substances  of  which  the  observer  has  no  knowledge. 

Without  going  into  the  history  of  nucleo-proteins  in  the  protoplasm  of  cells,  I 
may  say  that  they  are  not  nucleo-proteins  at  all,  but  lipoid-globuhns. 

The  marked  avidity  for  pyronin  which  both  the  nucleolus  and  the  protoplasm 
of  plasma  cells  show,  the  fact  that  they  are  both  resistant  to  reagents,  the  fact  that 
both  are  feebly  optically  active,  and  the  fact  that  both  have  feeble  reducing  pro- 
perties, brings  them  into  line  with  the  phases  of  the  Leucocytozoon  sypJiilidis.  The 
resemblance  is  only  superficially  close,  as  when  one  attempts  to  measure  the  degree 
of  resistance  to  reagents,  etc.,  the  protoplasm  of  the  plasma  cells  and  nucleoli  falls 
far  behind  that  of  the  parasitic  bodies.^ 

The  divisou  of  a  cell  is  dependent  upon  the  presence  of  this  lipoid-globuhn 
complex,  and  as  it  is  the  nucleus  which  is  concerned  in  this  process,  the  nucleolus 
is  found  in  the  nucleus,  and  not  in  the  protoplasm  of  the  cell. 


532  BIOLOGY   OF   INFLAMMATION   AND    MALIGNANT   DISEASE. 

The  lipoid-globulin  in  the  protoplasm  of  the  plasma  cell  is  present  for  quite  a 
different  purpose,  since,  when  the  protoplasm  of  a  plasma  cell  breaks  up,  and  it  often 
does  so  without  interfering  in  any  way  with  the  nucleus,  the  fragments  still  have 
the  properties  of  Hpoid-globulin.  The  function  of  a  plasma  cell  is  certainly  not 
phagocjiiic,  but,  from  analogy  to  other  cells  which  also  contain  hpoid-protein,  it 
would  appear  to  be  a  carrier  of  a  ferment,  the  function  of  the  ferment  being  to 
stimulate  or  to  activate  the  adsorptive  action  of  the  protein. 

The  plasma  cell  is  not  present  in  sj^hihs  only,  for  it  is  seen  in  any  chronic 
inflammation,  such  as  tuberculosis,  or  the  chronic  inflammation  which  may  be 
produced  by  a  piece  of  silk  or  wax. 

In  all  cases,  the  plasma  cell  is  morphologically  the  same,  and  although  its  gross 
action  may  be  similar  in  every  instance,  it  is,  nevertheless,  specific  in  each  case. 

Take,  for  example,  three  plasmomata,  one  caused  by  syphihs,  another  by 
tuberculosis,  and  the  third  by  a  foreign  body.  Give  an  injection  of  salvarsan,  and 
then  make  sections  of  all  three  again,  when,  on  examination,  it  will  be  found  that 
the  only  plasma  cells  which  have  altered,  are  those  of  syphilitic  origin. 

To  explain  this  specificity,  we  must  probe  the  chemistry  and  physico-chemistry 
of  the  plasma  cell,  and  this  has  been  fully  described  in  Chapter  VI. ;  there  is  no 
need  to  reproduce  it  again  here. 

All  my  recent  work  on  this  subject  leads  me  to  believe  that  specificity  rests 
in  the  way  in  which  the  Upoid-globulin  particles  are  built  up.  An  homologous 
stereo-chemical  molecular  configuration  exists  between  the  lipoid-globuUn  particles 
of  the  host  (some  are  in  the  plasma  cell)  and  those  of  the  parasite.  The  lipoid- 
globuUn  particles  of  the  host  constitute  his  protective  machine,  the  action  of  which 
is  to  destroy  the  Hpoid-globuHn  particles  of  the  parasite,  by  means  of  adsorption, 
and  consequent  precipitation,  and  ultimate  hydrolysis.  It  is  the  oxidising  ferments 
that  activate  the  adsorption. 

Degenerate  Forms  of  the  Plasma  Cell. 

I  will  now  pass  on  to  the  degenerate  forms  of  the  plasma  cell,  which  have  never 
been  fully  described  before,  although  Unna,  some  years  ago,  drew  attention  to 
them,^^  and  which  have  frequently  given  rise  to  faulty  histological  interpretations. 

"When  examined  in  vivo  (Plate  20),  stained  with  borax  methylene  blue,  large 
round  cells,  which  stain  red,  are  sometimes  to  be  seen.  They  may  contain  no 
nucleus,  or  the  nucleus  may  be  found  outside  the  cell,  lying  on  a  portion  of  its 
circumference.  In  some  of  the  cells,  dots,  masses  and  strands  may  be  seen,  which 
stain  with  the  methylene  violet,  and  are  situated  anywhere,  and  scattered  about 
i  rregularly  in  the  cell.     These  bodies  may  have  no  connection  with  the  nucleus 


«      »**© 

/■ 

i 

•A 

'9  ^ 

0 

% 


Plate  50. 


Crystalline  forms  of  aminoplasma  cells  from  a  syphilitic  lyni|ilin,tic  gland. 
The  section  has  been  stained  with  pjToniii  and  methyl  green. 


2. 

Section  of  a  lymphatic  gland  from  the  neck  of  a  rat  which  had  died  of 
trypanosomiasis.  Stained  with  pyronin  and  metliyl  green.  Note  the  dilated 
vessel,  with  endothelial  cells  in  the  lumen.  Similar  endothelial  cells  are  also 
to  he  seen  in  the  tissues  around.  Some  of  the  endothelial  cells  are  multi- 
nucleated ;  in  the  nucleus  of  others,  two  or  more  nucleoli  are  to  he  seen,  in 
a  few  the  nucleus  has  vanished  altogether,  and  in  aU,  the  chromatin  stains 
badly,  and  there  is  no  attempt  at  the  formation  of  lymphocytes.  Many  of 
the  plasma  cells  will  be  seen  to  have  two  or  more  nuclei.  Here  and  there  in 
the  section,  amorphous  pyroninophile  masses  are  visible  which  have  originated 
from  the  protoplasm  of  some  of  the  plasma  cells. 


Facing  p.  532 


.  -M-  ueuh 

any  clu 
l;ich  may 

06  aTAJ^^^'^'^''^®^^^'  specific  in  rnrh.  • 
Hiomata,  one  caused  by 
■ign  brfey.     Give  an  injection  oi  salva, 

.n-^OTj  IvriJ-Hii  Iirii:  (liiior/q  fitivr  fi9fii(i1>-.  ns-aJ  Bnil  noiJoee  sdT 

u'O-cher::' 

J',  ijiil)  buti >{■  <Ul4i  un  e^.^g  >l-)m  odJ   uionl  btiiilg  ailBiliimv.l  );  lo  rioiiaife 

fii  allao  iaihatobaf)  Airii  ,ha837 ' 

-i:!UIM      nK    ^iiv)     ij;lliliiul-li-.     -n,      n.     n.iwr.         LfUfOf*  83038**  8d*    HI  n6^  sdOi'' '■ 

(li  ,riooa  wi  .o*  o-wiloaloiiaaiom  ao  ow*  .eaodio  io  aasloun  9(t>  aL^jf^iitefi^w'^jr;!  r 

-■A.i.U  ai'tfiutcwlp  odJ  ,11^  oi  bus  .isiliogoJte  b9d8i(tJiY  sfid  auebuii  add  ■wsl- e    ;; 

oi'A&8'id'f6W^*i^|ji^^'^d^ 

b'jljJiiiMlTJ  ■■i>V(;il  il;lil/I  «iHlwiY'yH:  fcn-;^ii:ii  fiiriiqOf(afOItjq'g}JoBcfIOHLft'',!flB5ij9089ilJ 


interpi' 
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.SS3  .fK  Vt'^>o^ 


[©-Sis'     Q   ^   -     \ 


Plate  50. 


ROLE    PLAYED    BY    LYMPHOCYTE.  533 

and  the  larger  the  cell,  the  fewer  there  are  to  be  found,  and  in  many  of  the  largest 
cells  none  at  all  are  to  be  seen. 

In  fixed  .specimens  (Plate  23  (1,  2))  the  appearance  of  these  cells  is  very 
difJerent,  and  instead  of  being  round  homogeneous  cells,  they  are  often  irregular 
in  shape,  and  divided  up  into  irregular  sized  loculi,  or  balls  of  protoplasm,  many 
of  which  become  loose  and  scattered  about  in  the  tissue.  These  balls  stain  with 
safranin,  acid  fuschsin,  and  give  a  berlin  blue  reaction  with  a  mixture  of  potassium 
ferricyanide  and  ferric  chloride.  They  do  not  stain  well  with  pyronin,  but,  in  some 
specimens,  strands  of  protoplasm,  which  do  stain  with  pyronin,  are  to  be  noticed  in 
between  the  loculi.  The  strands  are,  no  doubt,  the  same  as  the  dots,  masses,  and 
strands,  which  were  described  in  the  in  vivo  method,  as  showing  an  affinity  for 
methylene  violet. 

The.se  ballooned  plasma  cells  have,  in  some  cases,  lost  their  nuclei,  while  in 
others,  the  nucleus  has  lengthened  out,  and  fits  one  apex  of  the  cell,  like  a  cap  does 
the  head,  and  not  infrecjuently  it  sends  string-like  processes  down  over  the  cell 
protopla.sm.  The.se  cells  are,  no  doubt,  degenerated  plasma  cells,  because  the 
protopla.sm  gives  amino-acid  reactions,  and  the  nucleus  fails  to  stain  with  methyl 
green,  owing  to  the  disappearance  of  the  nucleic  acid  radicle,  which  leaves  the 
protein  radicle  (histone  and  protamine)  behind. 

The  aminoplasma  cell  is  a  form  of  plasma  cell  which  Unna^^  has  called,  from 
his  examinations  thereof  in  fixed  specimens,  hyaline  plasma  cell.  The  term 
"  hyaline  "  rather  suggests  some  relationship  to  cartilage,  although  it  is  very  largely 
used  for  substances  of  which  the  observer  has  no  knowledge.  Now  hyaline 
cartilage  is  a  strongly  basophilic  substance,  owing  to  its  chondroitin  sulphuric  acid 
radicle.  Unna's  hyaline  plasma  cells  are,  on  the  other  hand,  acidophilic,  and 
contain  no  acid  radicle  ;  furthermore,  they  have  very  strong  reducing  properties, 
and  so  cannot  stain  with  methyl  green,  and,  as  I  have  shown  that  this  reducing 
action  is  due  to  tryosine  or  trypophane,  I  consider  that  the  best  name  for  them 
is  aminoplasma  cells.  The  cells  are  frequently  to  be  met  with  in  syphilitic 
material,  but  they  are  also  to  be  found  in  any  very  chronic  inflammatory  lesion, 
viz.,  RJiinoscleroma  and  Ulcus  molle  serpiginosum. 

It  rarely  occurs  that  plasma  cells  degenerate  into  crystalline  forms  (Plate  50  (1)), 
either  as  .sheaves  or  as  rectangular  prisms.  The  nucleus  in  these  cases  remains 
intact,  and  stains  fairly  well  with  methyl  green,  and  this  is  not  invariably  the  case 
in  the  aminoplasma  cells,  a  point  which  suggests  that  the  crystalline  degeneration 
is  higher  in  the  scale  than  the  amino-acid  degeneration.  Further  examinations 
also  bear  this  out,  because  the  crystals  stain  better  with  pyronin,  and  they  have 
a  feeble  reducing  action  in  comparison  with  the  ordinary  aminoplasma  cells. 


534  BIOLOGY   OF   INFLAMMATION   AND    MALIGNANT   DISEASE. 

If  a  cell  degenerates,  the  products  formed  thereby  must  be  chemical  entities, 
which  probably  do  not  differ  from  those  formed  in  the  process  of  digestion.  Between 
the  albumose  and  amino-acid  stages,  one  finds  the  polypeptides  ;  therefore,  as 
these  crystalline  cells  are  not  so  degenerate  as  the  aminoplasma  cells,  one  is  tempted 
to  call  them  polypeptide  cells,  since  we  are  all  aware  that  polypeptides  can  exist 
in  the  crystalline  form. 

Summary. 

A  lymphocyte  originates  from  endothelial  cells.  A  lymphocyte  gives  rise 
to  plasma  cells.  The  function  of  a  plasma  cell  is  to  protect  its  host  against  an 
enemy,  by  adsorping  his  specific  lipoid-globuUn,  which  results  in  his  disintegration, 
and  this  adsorption  phenomenon  is  activated  and  stimulated  by  oxydising  ferments, 
which  are  ever  present,  but  are  not  specific.  Plasma  cells  undergo  degeneration 
into  polypeptide  and  aminoplasma  cells,  the  latter  form  being  hitherto  regarded  as 
hyaline  degeneration. 

The  Parts  which  Lymphocytes  and  Plasma  Cells  Play  in  Disease. 

Let  us  now  turn  our  attention  to  the  study  of  the  lymphocyte  in  disease,  and 
note  the  morphological  changes  it  and  the  plasma  cell  undergo  in  inflammation, 
in  the  so-called  leucaemic  affections,  and  in  sarcoma. 

(a)  Inflammation. 

In  inflammation,  a  phenomenon  which  may  be  caused  by  various  diverse 
factors,  one  sees  a  lymphocytic  and  plasma-celled  infiltration,  which  disappears 
when  the  cause  of  the  inflammation  vanishes.  Supposing,  on  the  other  hand,  that 
the  cause  does  not  vanish,  and  that  the  host  dies  as  the  result  thereof,  is  there  any 
difference  in  the  morphological  characters  of  the  protecting  cells  ? 

A  plasma  cell  infiltration,  par  excellence,  is  to  be  seen  in  protozoal  infections  ; 
therefore,  to  get  cases  which  have  succumbed  to  the  infection,  I  have  had  to  use 
rats  which  have  died  of  sleeping  sickness — material  with  which  the  London  School 
of  Tropical  Medicine  very  kindly  supplied  me.  I  have  chosen  chiefly  lymphatic 
glands  for  my  study  throughout  this  part  of  the  work,  because  they  may  be  looked 
upon  as  one  of  the  best  measurements  of  the  protective  capacity  of  the  host. 

Plate  50  (2)  is  a  section  of  a  lymphatic  gland  removed  from  the  neck  of  a  rat 
which  died  of  trypanosomiasis. 

One  notices  first  of  all  a  marked  dilatation  of  a  lymphatic  vessel,  with  numerous 
free  endothelial  cells  in  its  lumen.  In  the  surrounding  tissue,  there  are  also  many 
endothelial  cells.     There  is  a  well-marked  plasmoma,   in  which  the  plasma  cells 


ROLE    PLAYED    BY   LYMrHOCYTE.  535 

show  a  distinct  change,  from  the  normal,  in  that  the  nuclei  are  freely  dividing,  and, 
in  some  cells,  even  three  and  four  nuclei  are  discernible. 

This  picture,  I  feel,  should  be  interpreted  in  the  following  light :  Owing  to  the 
demand  upon  protective  cells,  those  already  formed  are  doing  their  best  to  multiply 
of  their  own  accord  to  form  double,  treble,  or  quadruple  the  number  of  plasma 
cells  by  simple  amitotic  division.  More  plasma  cells  have  to  be  formed,  so  there 
will  have  to  be  a  heavy  production  of  lymphocytes,  and  this  necessitates  prunarily 
an  increase  in  the  number  of  endothehal  cells. 

In  any  infection,  the  cause  thereof  will  be  combated  first  by  those  cells  which 
are  already  formed  ;  if  these  suffice  to  conquer,  then  all  is  well.  If,  on  the  other 
hand,  they  lose,  they  will  have  to  call  up  their  reserve  forces,  but  in  the  meantune 
they  will  make  an  extra  effort  of  tlieir  own,  by  trying  to  multipl}'.  Therefore,  in  a 
very  severe  infection  which  speedily  causes  the  death  of  the  host,  you  will  get  the 
multiplication  of  the  forces  already  there,  also  an  increase  of  the  forces  at  the  base, 
but  the  latter  will  be  prevented  from  coming  to  the  front ;  hence  the  reason  why, 
in  this  section,  the  endothelial  cells  are  not  to  be  found  in  the  active  condition  of 
manufacturing  lymphocytes,  why  many  of  them  contain  more  than  one  nucleus, 
and  why  very  few  lymphocjrtes  are  to  be  seen. 

(b)  Leucaemia. 

The  term  "  leucaemia  "  is  an  unfortunate  one,  as  it  means  only  leucocytes  in 
the  blood.  Now,  leucocj^tes  are  not  manufactured  in  the  blood,  therefore  they 
must  be  formed  somewhere  before  they  can  get  into  the  blood  stream.  They  may 
be  formed  in  many  places,  viz.,  in  the  lymphatic  glands,  spleen,  and  bone-marrow. 
However  many  are  formed  in  the  first  two  organs,  none  will  get  into  the  general 
circulation,  this  being  the  case  only  when  the  bone-marrow  is  the  depot.  Since  the 
cause  of  leucaemia  does  not  necessarily  attack  the  bone-marrow  first,  it  is  at  once 
seen  that  the  blood-picture  can  only  be  a  symptom  of  the  disease,  and  it  may  be 
either  absent  or  present.  Therefore  a  patient  may  suffer  from  leucaemia  for  years, 
without  there  being  any  change  in  the  blood  at  all.  Hence  the  reason  why  I  have 
chosen  the  lymphatic  gland  as  the  best  organ  in  which  to  study  the  lymphocyte, 
because,  in  practically  all  conditions  affecting  lymphocytes,  the  lymphatic  gland 
plays  a  role.  The  leucaemias  are  generally  divided  into  three  main  types  :  (a) 
lymphatic  leucaemia  ;  (6)  myeloid  leucaemia  ;  (c)  pseudo-leucaemia.  Lymphatic 
and  myeloid  leucaemias  never  mix,  i.e.,  one  form  never  runs  into  the  other. 
Myeloid  tissue  is,  in  adults  at  all  events,  limited  to  the  bone-marrow,  and  when 
myeloid  tissue  has  been  found  in  the  skin,  lymphatic  glands,  spleen,  etc.,  it  has 
either  arrived  there  as  a  metastasis,  or  has  been  formed  in  loco  as  a  metaplasia. 


536  BIOLOGY   OF   INFLAMMATION    AND    MALIGNANT   DISEASE. 

Whether  both  views  are  possible,  or  only  one,  does  not  at  present  concern  me  ;  but 
I  would  like  to  make  the  remark  that  many  of  the  so-called  myeloid  metaplasias 
in  the  lymphatic  glands  are  not  myelocytes  at  all,  but  merely  endothelial  cells 
such  as  are  depicted  in  Plate  50  (2). 

It  is  more  than  probable,  that  the  endothelial  cells  of  Kanphatics,  or  such  as 
one  sees  in  large  numbers  in  Ipiiphatic  glands,  are  analogous  to  the  myeloblasts 
of  the  bone-marrow.  In  both  instances,  they  are  the  parents  of  leucocytes.  One 
of  the  most  important  points  which  a  repeated  examination  of  leucaemic  tissue  has 
brought  out,  is  the  tendency  of  the  affected  cell  to  approach  to  its  embryonic 
morphology,  a  point  which  is  strongly  in  favour  of  a  probable  bridge  between 
leucaemia  and  sarcoma. 

The  peculiar  localisation  of  the  leucaemic  process  is  again  another  suggestion 
of  a  relationship  between  leucaemia  and  sarcoma. 

Owing  to  the  fact  that  a  case  of  lymphatic  leucaemia  may  begin  without  any 
attendant  changes  in  the  blood  at  all,  but  simply  as  an  enlargement  of  one  or  more 
groups  of  lymphatic  glands,  the  term  "  lymphadenosis  "  has  been  frequently  used 
instead  of  Ijonphatic  leucaemia.  Up  to  the  present,  lymphadenosis  appears  to  be 
the  better  name,  as,  by  using  it,  such  terms  as  the  "  pseudo-leucaemia  of  Pinkus," 
the  "  aleucaemia  of  Pappenheim,"  etc.,  are  avoided,  provided  that  it  always  be 
remembered  that  the  disease  may  at  any  time  develop  the  t}'pical  blood-picture  of 
lymphatic  leucaemia.  Unfortunately,  the  English  have  a  term  "  Ijnnphadenoma," 
which  means  a  new  growth  of  lymph  gland  tissue.  It  is  used  to  designate  enlarged 
glands,  which  upon  examination  show  no  evidence  of  having  increased  in  size,  due 
to  inflammation,  such  as  might  be  caused  by  tubercle,  etc. 

With  many  observers,  lymphadenoma  and  Hodgkin's  disease  are  two  names 
for  the  same  condition. 

The  lymphadenoma,  as  seen  by  the  English,  is  never  followed  by  changes  in 
the  blood,  such  as  are  met  with  in  lymphatic  leucaemia.  Therefore  confusion 
may  easily  arise,  when  the  same  term  is  applied  in  England  and  on  the  Continent 
to  apparently  widely  different  conditions. 

Is  it  not  possible  that  these  various  types  are  links  in  one  chain  of  events, 
along  which  we  can  trace  the  connections,  as  was  done  in  Chapter  XLV.,  between 
inflammation  and  new  gro\\i:h  of  epithelial  tissue  ? 

An  enlargement  of  lymphatic  glands  may  result  from  inflammation  ;  if  the 
cause  of  the  inflammation  is  continuous,  other  stations  along  the  line  may  be 
attacked. 

The  stations  along  the  line  in  which  lymphoc3'tes  are  formed  may,  for  sake  of 
convenience,     be     divided    into     three  :      (1)     lymphatic     glands ;      (2)     spleen  ; 


ROLE    PLAYED    BY    LYMPHOCYTE.  537 

(3)  boue-maiTOw.  It  is  well  known  that,  in  persistent  inflammation,  the  body  is 
continually  drawing  upon  its  reserve  forces,  until  the  most  important  and  the  last 
card  is  played. 

If  station  (1)  is  attacked,  there  will  merely  be  an  enlargement  of  one  or  more 
groups  of  lymphatic  glands,  to  accommodate  the  increased  local  production  of 
lymphocytes.  However  severely  station  (1)  may  be  attacked,  i.e.,  however  large 
the  glands  may  get,  no  lymphocytes  get  into  the  general  circulation.  If  the 
inflammation  continues,  and  the  lymphatic  glands  can  do  no  more,  the  next  station 
— the  spleen — is  attacked.  To  whatever  size  the  spleen  may  be  enlarged,  none  of 
the  lymphocx'tes  formed  therein  reach  the  general  blood  stream.  If  the  inflam- 
mation still  continues,  station  (3)  is  attacked,  and  when  that  is  the  case,  the 
lymphocytes  formed  in  the  bone-marrow  find  their  way  into  the  circulation. 

So  long  as  only  stations  (1)  and  (2)  are  affected,  the  condition  is  one  of 
lymphadenosis  ;  when  station  (.'))  is  involved,  the  condition  becomes  lymphatic 
leucaemia. 

The  course  just  depicted  diagrammatically,  is  also  frequently  seen  to  be  the 
same  clinically.  A  patient  complains  of  enlargement  of  the  lymphatic  glands — 
blood-picture  normal.  Later,  the  spleen,  and  perhaps  the  liver,  become  enlarged, 
blood-picture  still  normal.  Gradually  the  lymphocytes  in  the  blood  increase, 
absolutely  and  relatively,  until  the  white  blood  corpuscles  are  composed  of  nothing 
but  lymphocytes,  when  the  patient  dies.  Post-moHem,  the  bone-marrow  is  found 
to  be  affected. 

Station  (1)  is  not  always  the  first  affected  ;  it  may  be  station  (2)  or  station  (3). 
Clinically,  cases  have  been  described  in  which  there  was  an  enormous  enlargement 
of  the  spleen,  with  little  or  no  enlargement  of  the  lymphatic  glands,  and  with  a 
normal  blood  picture,  which  later  developed  the  typical  blood  count  of  l}'mphatic 
leucaemia.  If  station  (3)  is  affected  first,  the  disease  runs  an  extremely  rapid 
course,  often  killing  the  patient  in  a  few  weeks.  In  such  cases,  the  blood-picture 
is  present  from  the  start,  and  there  may  be  little  or  no  enlargement  of  the  spleen 
and  the  lymphatic  glands. 

It  would  appear  from  the  foregoing,  that  of  the  three  stations  the  third  was- 
the  most  important ;  in  other  words,  the  base,  in  which  operations  were  not 
carried  on  by  the  host  until  the  resisting  capacity  of  the  Ijnnphatic  glands  and 
spleen  had  been  overcome.  As  the  base  may  be  primarily  attacked,  it  would  not  be 
of  much  avail  to  call  upon  the  other  two  stations  for  assistance,  hence  the  glands 
and  spleen  are  usually  not  involved  to  any  great  extent  when  such  is  the  case.  It 
might  be  said  that  when  the  bone-marrow  is  affected,  the  patient  dies  before  the 
glands  and  spleen  have  had  time  to  come  to  the  rescue,  but,  in  support  of  the  view 


538  BIOLOGY    OF   INFLAMMATION    AND    MALIGNANT   DISEASE. 

that  they  are  of  minor  importance,  is  the  fact  that  when  station  (2)  is  attacked 
first,  the  lymphatic  glands  do  not,  as  a  rule,  become  implicated,  and  when  the  attack 
continues,  it  is  the  bone-marrow  that  comes  to  the  rescue,  and  not  the  glands. 

AATiether  the  cause  of  inflammation  which  gives  rise  to  that  group  of  lymph- 
adenosis, ending  in  lymphatic  leucaemia,  is  always  the  same,  or  whether  there  is 
more  than  one  cause,  or  what  the  cause  or  causes,  are  by  no  means  settled. 

(c)  Sarcoma. 

The  epithelial  cells  nndtiply  in  inflammation  ;  they  may  also  multiply  when 
there  is  no  inflammation,  when  they  constitute  what  is  called  a  new  growth. 

The  same  with  the  lymphocji^e.  Lpnphocytes  may  multiply  rapidly  in 
inflammation,  or  they  may  multiply  rapidly  after  the  nature  of  a  new  growth. 

If  the  cells  of  a  Ijmiphatic  gland,  or  a  group  of  lymphatic  glands,  take  on  the 
characteristics  of  new  growth,  when  a  certain  number  have  been  formed,  they  will 
break  through  the  capsule  of  the  gland,  invade  all  neighbouiing  organs,  and  give 
rise  to  metastases.  The  cause  of  the  initial  onset  of  the  new  growth  fonnation  is 
unknown  ;  but,  nevertheless,  its  action  is  generally  highly  localised,  with  the  result 
that  the  spleen  and  bone-marrow  are  never  called  upon  to  assist,  which  means  that 
there  will  be  no  increased  lyniphocj'tosis. 

Lymphadenosis  could  be  divided  into  two  classes  :  («)  inflammatory  lymph- 
adenosis ;   (6)  new  growth  lymphadenosis. 

The  most  interesting  point  that  now  arises  is,  whether  there  is  any  connection 
between  these  types  of  lymphadenosis  ;  if  so,  then  the  lymphocytic  chain  is 
complete. 

As  the  inflamed  epithehum  in  a  chancre  or  a  gumma  may  assume  malignant 
characteristics,  therefore,  if  there  is  a  connecting  link  between  the  two  types  of 
lymphadenosis,  it  will  be  found  in  the  inflammatory  class,  i.e.,  the  lymphocytes 
in  a  gland  from  a  case  of  inflammatory  lymphadenosis  will  become  converted  into 
a  new  growth  lymphadenosis. 

Clinically  it  may  be  easy  to  tell  when  a  malignant  epithelioma  develops,  but 
it  is  not  so  in  the  case  of  a  maUgnant  lymphadenoma.  In  both  cases,  a  microscopic 
examination  is  generally  necessary  to  settle  the  diagnosis.  One  point  which 
suggests  malignancy  in  epithelial  tissue  is  the  invasion  of  the  corium  by  the 
epithelial  cells.  Invasion,  in  the  case  of  a  Ijmiphatic  gland,  occurs,  but  it  is  not 
easy  to  recognise.  Moreover,  the  capsule  thickens  when  the  gland  enlarges,  and 
acts  as  a  protective  barrier  for  some  time.  Histological  examination,  and  a  close 
study  of  the  lymphocytes,  is  the  only  means  of  telling  whether  the  enlargement 
of  a  gland  is  due  to  inflammation,  or  to  a  new  growth.     Before  describing  the 


EOLE    PLAYED    BY    LYMPHOCYTE.  539 

lymphocyte  in  lymphadenosis,  I  would  just  like  to  call  attention  to  the  fact  that 
myeloid  leucaemia  may  be  divided  up  like  lymphatic  leucaemia. 

The  myelosis  can  be  separated  into  inflammatory  myelosis  and  new-growth 
myelosis.  In  the  former,  myelocytes  are  found  in  the  blood,  but  not  so  in  the 
latter.  The  inflammatory  type  may  run  an  acute  or  chronic  course,  and,  in  every 
other  detail,  myelosis  may  be  found  to  resemble  lymphadenosis,  and  connecting 
links  exist  between  the  inflammatory  and  new-growth  types  of  both. 

With  epithelimii,  it  is  noticed  that  different  irritants  affect  different  epithelial 
cells.  The  sun's  rays,  for  instance,  seem  to  affect  the^lowest  layers  for  preference, 
as  the  epithelioma  resulting  therefrom  closely  resembles  a  rodent  ulcer.  The 
X-rays,  on  the  other  hand,  seem  to  affect  the  upper  layers,  as  horny  tissue  and 
cell  nests  are  the  main  features  of  the  epithelioma. 

This  is  likewise  the  case  with  the  IjTnphocyte.  It  may  be  attacked  while  a 
plasma  cell,  while  a  lymphocj-te  just  after  it  has  left  the  endothelial  cell,  and  even 
the  endothelial  cell  itself  may  be  affected. 

In  the  inflammatory  lymphadenosis,  the  lymphoc3rtes  are  increased  in  loco  ; 
if  the  cause  of  the  inflammation  continues,  not  only  the  spleen  and  bone-marrow 
try  to  come  to  the  rescue,  but  the  cells  themselves  in  the  primarily  affected  glands 
will  make  every  effort  to  protect  the  host.  Therefore,  in  different  cases  there  will 
be  a  different  call  upon  the  various  phases  in  the  life  history  of  the  Ijnnphocyte, 
so  that  even  the  parent  cells  may  be  involved. 

Therefore,  in  the  inflammatory  cases,  the  increase  of  the  cells  will  not  necessarily 
be  all  of  one  type,  as  is  the  rule  in  the  new  growth  cases. 

As  will  be  seen  later,  all  the  phases  in  the  life  history  of  the  lymphocyte  are 
not  invariably  involved,  however  persistent  be  the  action  of  the  irritant.  Anj'-  one 
phase  may  take  upon  itself  to  multiply,  in  such  a  way  that  it  constitutes 
malignancy. 

Therefore,  the  difference  between  inflammatory  and  malignant  lymphadenosis 
will  not  depend  upon  whether  the  growth  invades  healthy  tissue  or  not,  since  more 
often  than  not  invasion  cannot  bo  determined  ;  but  it  will  depend  upon  whether 
the  phases  in  the  life  history  of  the  lymphocyte  from  plasma  cell  to  endothelial- 
cell  come  to  the  rescue  in  their  turn,  should  their  help  be  required,  or  upon  w'hether 
any  one  phase  takes  the  whole  protective  work  upon  itself.  The  foniier  signifies 
inflammation,  the  latter  malignancy,  but  when  the  histological  details  of  the  various 
phases  are  dealt  with,  it  will  be  seen  that  a  hard  and  fast  line  between  inflam- 
mation and  sarcoma  does  not  exist.  In  other  words,  it  will  be  seen  that  there  is  a 
chain,  the  first  link  of  which  is  inflammation,  and  the  last  link  of  which  is  sarcoma, 
and  that  there  are  other  Unks  in  between  which  comiect  the  two. 


540  BIOLOGY    OF   INFLAMMATION   AND    MALIGNANT   DISEASE. 

If  l)Tiiphatic  glands  are  removed  from  cases  of  lymphadenosis,  both  from  the 
clinically  inflammatory  and  from  the  new-growth  types,  it  will  be  found,  when  they 
are  examined  histologically,  that  scarcely  any  two  are  exactly  alike.  In  many 
cases  it  is,  moreover,  impossible  to  distinguish  between  a  gland  removed  from  a 
case  of  inflammatory  lymphadenosis,  and  one  removed  from  a  case  of  malignant 
l)rmphadenosis.  The  extreme  types  of  each  condition  are  easily  distinguished, 
and  as  their  characteristics  are  to  be  found  in  all  the  text-books  deahng  with  the 
subject,  I  only  propose  to  refer  to  the  intermediary  types.  The  more  chronic  the 
condition,  the  longer  the  structure  of  the  gland  will  be  maintained,  and  the  less 
likelihood  will  there  be  of  the  parent  cell  being  called  upon  to  assist. 

The  more  acute  the  condition,  the  less  will  the  structure  of  the  gland  be 
maintained,  and  the  greater  will  be  the  call  upon  the  endothehal  cells.  Since  the 
endothelial  cells  are  to  be  found  in  the  follicles,  it  will  stand  to  reason  that  in  some 
of  the  acute  glands  only  follicles,  or,  better  to  say,  only  foUicular-hke  tissue  is  seen. 
In  the  still  more  acute  glands,  the  follicles  are  all  broken  up  and  the  gland  merely 
consists  of  irregularh^  scattered  and  irregularly  formed  cells,  not  necessarily  many 
in  number ;  on  the  contrary,  there  are  less  than  might  be  expected.  Connective 
tissue  strands  are  to  be  found  amongst  the  cells. 

Naturally,  cases  are  to  be  met  with  between  the  chronic  and  acute  forms,  and 
a  chronic  case  may  suddenly  become  acute.  It  is  with  these  intermediary  forms 
that  the  malignant  type  is  to  be  most  frequently  confused,  the  distinction  being 
often  impossible. 

In  the  so-called  chronic  lymphadenosis,  the  capsule  of  the  gland  may  be 
infiltrated  with  lymphocytes,  and  these  cells  may  even  be  found  in  the  surrounding 
glandular  tissue.  The  same  appearances  are  to  be  met  with  in  glands  removed  from 
cases  of  Hodgkin's  disease  and  from  the  so-called  lymphosarcomatosis.  In  chronic 
inflammatory  lymphadenosis,  but  more  often  in  the  subacute  form,  enormous 
numbers  of  endothelial  cells  may  be  seen,  giving  birth  to  Ijinphocytes.  These  are 
also  to  be  seen  in  glands  from  Hodgkin's  disease.  In  both  cases  plasma  cells  are 
to  be  found,  some  of  which  are  dividing  and  subdividing.  Primary  and  secondary 
division  of  lymphocytes  is  to  be  seen,  and,  in  some  cases,  the  nucleoli  of  the 
lymphocyte  are  found  to  be  enormously  increased  in  size,  and  often  in  number,  in 
the  one  cell. 

If  my  remarks  upon  the  pseudo-parasites  of  malignant  epithelioma  are  referred 
to  (Chapter  XLV.),  it  will  be  noticed  that  the  pseudo-parasite  was  the  nucleolus, 
which,  after  being  discharged  from  the  cell,  took  upon  itself  parasitic  characters 
by  dividing  and  subdividing,  both  by  mitosis  and  amitosis,  after  the  budding 
fashion. 


ROLE    PLAYED  BY   LYMPHOCYTE.  541 

Although  the  various  phases,  which  one  of  the  iUustratioiis  .shows  as  occurring 
in  mahgnant  epithehouia,  appear  to  be  perfectly  regular  and  straightforward,  they 
are  by  no  means  so  in  every  case  of  malignant  epithehoma,  and  although  the  .same 
process  may  be  witnessed  in  both  inflammatory  lymphadenosis  and  Hodgkin's 
disease,  it  is  still  less  regular  and  straightforward. 

Now  Hodgkin's  disease  is  no  doubt  ultimately  a  mahgnant  disease  of  the 
lymphatic  glands.  No  two  glands  are  microscopically  the  same,  and  frequently 
the  histological  characters  are  identical  with  those  from  a  case  of  inflammatory 
lymphadenosis,    which    ultimately    ends    in     lymphatic    leucaemia. 

Therefore,  it  can  be  said  that  there  is  no  hard  and  fast  line  between  hyperplasia 
and  lympho-sarcomatous  growth.  After  all,  there  is  no  .sharp  distinction  between 
inflammation  and  malignancy,  and  the  main  determining  point  appears  to  be  as 
to  whether  the  further  phase  is  called  up  to  protect,  or  whether  the  nucleolus  of  the 
phase  affected  takes  upon  itself  the  sole  responsibihty. 

As  the  nucleoli  of  lymphocytes  may  behave  p.seudo-parasitically,  in  what 
we  clinically  call  inflammatory  lymphadenosis,  it  is  at  once  clear  that,  when  such 
is  the  case,  the  case  is  really  malignant. 

In  .support  of  the  statement  above  mentioned,  i.e.,  that  a  case  of  lymphatic 
leucaemia  may  really  be  malignant  in  the  latter  stage  of  its  course,  mention  need 
only  be  made  of  the  chloromata,  or,  as  they  are  frequently  called,  the  chloro- 
lymphadenoses.  Chloromata  have,  by  most  observers,  been  looked  upon  as 
malignant  growths,  but  since  they  are  so  frequently  associated  with  blood  changes 
which  are  characteristic  of  lymphatic  and  myeloid  leucaemias,  they  may  be 
equally  regarded  as  inflammatory  growths.  There  are  two  forms  of  chloromata — the 
lymphatic  and  the  myeloid.  Both  may  run  an  aleucaemic  course,  and  not  differ 
from  the  analogous  condition.s — Hodgkin's  disease  and  new-growth  myelosis— 
while,  on  the  other  hand,  although  clinically  and  histologically  the  same,  they  may 
run  a  leucaemic  course,  thereby  simulating  inflammatory  lymphadenosis  and 
myelosis. 

As  we  shall  soon  see,  lymphadenosis  is  occa.sionally  accompanied  by  skin 
lesions  ;  such  is  the  case,  although  much  more  rarely,  with  chloro-lymphadenosis. 
The  green  colour  is  not  necessarily  seen  in  every  hyperplasia,  or  metastasis  in  every 
case  of  chloroma,  which  strongly  suggests  that  the  condition  is  not  originally  an 
entity,  but  only  becomes  so  when  the  cells — lymphocytes  and  myelocytes — undergo 
some  chemical  change  to  which  the  green  colour  is  due.  The  colour  rapidly 
disappears,  but  is  restored  again  by  HnO.,  a  fact  which  permits  one  to  theorise  that 
the  green  colour  is  due  to  an  oxydase  reaction  upon  the  protein,  or  Upoid-protein 
molecule   of     the  cell.     I   have   noticed   a   similar   green   colour   result  from  the 


542  BIOLOGY   OF  INFLAMMATION  AND   MALIGNANT  DISEASE. 

oxidation  of  protagon  and  cerebrin  adsorption  compounds  with  globulin.  Fortunately, 
and  unfortunately,  the  condition  is  so  rare  that  an  exhaustive  chemical  investigation 
is  not  easily  to  be  pursued. 

PSEUDO-LEUCAEMLA. 

We  can  now  pass  on  to  the  so-called  pseudo-leucaemias. 

The  supposed  difference  between  pseudo-leucaemia  and  leucaemia  rests  upon 
whether  there  are  changes  in  the  blood,  or  not.  There  is  no  histological  difference 
in  the  skin  or  glandular  lesions  of  the  two  conditions,  and  since  a  case  of  leucaemia 
may  run  an  aleucaemic  course  for  months,  or  even  for  years,  it  looks  as  if  the 
difference  is  purely  arbitrary. 

Clinically,  it  would  appear,  at  first  sight,  that  the  division  of  the  two  conditions 
is  justifiable,  but  when  the  reason  which  accounts  for  the  different  clinical  pictures 
is  explained,  it  will  be  readily  seen  that  the  pseudo-leucaemias  are  merely  some  of 
the  links  in  my  lymphocytic  chain. 

If  the  term  "  pseudo-leucaemia  "  is  applied  to  those  conditions  in  which  the 
histological  appearances  of  the  lymphatic  glands  are  the  same,  but  only  to  that 
class  which  to  the  end  runs  an  aleucaemic  course,  Hodgkin's  disease  must  be 
included  therein.  To  my  mind,  Hodgkin's  disease  partly  resembles  lymphatic 
leucaemia,  with  one  main  difference,  that  the  lymphocytes  in  loco  assume  malignant 
characters  in  the  former,  while  in  the  latter,  before  the  lymphocytes  assume 
malignant  characters,  the  spleen  and  bone-marrow  come  to  the  rescue. 

A  clinical  entity  of  the  group  of  pseudo-leucaemias  is  Miculicz's  disease,  in 
which  a  leucaemic  infiltration  of  the  eyelids,  cheeks,  orbits,  lachrymal,  salivary, 
and  mannnary  glands  occurs. 

Here  we  have  the  first  indication  of  a  lymphocytic  growth  occurring  elsewhere 
than  in  the  lymphatic  glands,  spleen,  or  bone-marrow.  Many  skin  diseases  com- 
mence as  a  l)niiphocytic  growth,  during  the  course  of  which  the  lymphatic  glands 
become  enlarged.  If,  then,  an  irritant  makes  itself  felt  first  in  the  skin,  and  the 
irritant  happens  to  be  one  which  gives  rise  to  the  formation  of  lymphocytes  only, 
it  stands  to  reason  that  a  long  time  may  have  to  elapse,  before  the  spleen  and  the 
bone-marrow  are  called  upon  as  last  resources.  The  risk  of  such  a  case  dying,  before 
the  bone-marrow  is  affected,  is  greater  than  when  the  disease  starts  in  the  lymphatic 
glands;  therefore,  it  can  easily  be  understood  that  it  would  only  be  natural  for  a 
leucaemic  affection  of  the  skin  to  run  an  aleucaemic  course  for  a  considerable  period. 
Just  as  the  lymphocytic  growth,  starting  in  the  Ivmphatic  glands,  may  assume 
malignant  characteristics  as  an  extra  protective  measure,  as  is  seen  in  Hodgkin's 
disease,  so  may  the  lymphocytic  growth  which  starts  in  the  skin. 


I 


ROLE   PLAYED    BY   LYMPHOCYTE.  543 

As  the  lymphocytic  growth  in  a  lymphatic  gland  may  be  malignant  from  the 
start,  as  in  Ipnphosarcomatosis,  so  may  the  lymphocytic  growth  in  the  skin. 
Therefore,  the  same  events  may  take  place  in  the  skin  as  in  the  lymphatic  glands ; 
in  other  words,  the  leucaemic  conditions  of  the  two  are  analogous.  There  is  less 
likeUhood  of  the  skin  form  running  a  leucaemia  course,  but  it  is  possible,  therefore 
the  term  "  pseudo-leucaemia  "  may  become  ambiguous.  One  of  the  reasons  why 
this  subject  is  so  difficult  to  render  intelligible,  is  because  the  word  leucaemia  is 
used  to  mean  only  part  of  what  it  really  imphes.  If  the  myelocytes  and  the  lympho- 
cytes in  the  blood  are  increased,  the  condition  is  called  leucaemia,  provided  only 
that  the  cUnical  condition  is  of  a  certain  nature.  However  big  be  the  increase  of 
lymphoc}i;es  in  the  blood,  say,  for  instance,  in  a  case  of  syphihs,  the  terra  leucaemia 
cannot  be  used.  However  marked  be  the  eosinophiha,  even  in  a  case  of  lympho- 
cj^oma,  the  terra  leucaemia  cannot  be  employed. 

It  would  probably  be  better  to  drop  the  term  pseudo-leucaemia  altogether, 
to  do  away  also  with  the  word  lymphadenosis,  and  to  adopt  the  classification 
shown  on  page  544. 

LyMPHOCYTOM  ATA . 

A  lymphocytoma  may  begin  in  the  skin,  other  organs  of  the  body,  lymphatic 
glands,  spleen,  or  bone-marrow.  In  all  cases  but  the  last,  it  may  run  a  leucaemic 
or  an  aleucaemic  course.  The  leucaemic  course  ends  fatally,  and  so  quickly  that 
no  true  division  between  benignity  and  mahgnancy  is  possible  or  necessary,  since 
the  cells  in  any  case  finally  take  on  raahgnant  characters. 

AVith  the  aleucaeraic  Ijanphocytomata  the  case  is  different  ;  the  condition 
may  be  primarily  innocent  or  primarily  malignant  (sarcoma).  Intennediary  stages 
exist,  such  as  Mycosis  fungoides  in  the  case  of  the  skin,  and  Hodgkin's  disease  in 
the  case  of  the  lymphatic  glands. 

It  is  the  study  of  Mycosis  fungoides,  Lymphodermia  perniciosa,  and  Hodgkin's 
disease  which  enables  one  to  make  a  chain  consisting  of  several  links,  of  which  the 
first  is  an  inflammatory  lymphocytoma,  and  the  last  a  raahgnant  lymphocytoma — 
a  mesoblastic  chain  analogous  to  my  epiblastic  chain. 

We  come  now  to  describe  the  various  skin  lesions  to  be  met  with.  They  will 
naturally  fall  into  two  classes  :  («)  Those  which  start  in  the  skin,  true  lympho- 
cytomata  ;  (6)  those  which  are  secondary  to  lymiihocytomata,  which  have  com- 
menced elsewhere,  i.e.,  symptomatic.  We  will  consider  the  latter  first,  as,  from  our 
point  of  view,  they  are  relatively  ununportant.  In  cases  of  chronic  inflammatory 
lymphocytomata  the  patient  frequently  complains  of  itching,  the  skin  is  usually 
dry,   and    occasional  attacks  of    Urticaria    papulosa    et  vesiculosa   arise.      If  the 

2  M 


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BIOLOGY   OF   INFLAMMATION   AND   MALIGNANT    DISEASE. 


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ROLE    PLAYED    BY    LYMPHOCY^TE.  545 

itching  is  intense,  the  urticarial  wheals  may,  owing  to  scratching  and  the  secondary 
infection  arising  therefrom,  become  converted  into  small  granulation  tumours, 
which  in  tune  spontaneously  disappear.  In  cases  of  acute  inflammatory  Icucaemic 
l}inphocytomata,  the  most  common  skin  lesion  is  a  haemorrhagic  one,  in  the  form 
of  petechiae,  which,  in  some  cases,  become  so  big  that  the  skin  ov^^  them  necroses. 
Of  the  true  cutaneous  lymphocytomata  there  are  several  varieties,  and  although, 
chnically,  two  cases  are  alike,  a  normal  blood-count  may  be  obtained  from  one,  and 
from  the  other  a  hmiphocytosis,  or  a  marked  eosinophilia ;  in  other  words,  the 
lesions  belonging  to  the  leucaemic  and  aleucaemic  divisions  are  in  many  other  ways 
the  same. 

Leucaemia  Cutis. 

This  condition  is  characterised  by  swellings  in  the  skin,  which  vary  from  the 
size  of  a  small  pea  to  that  of  a  pigeon's  egg,  and  bigger.  They  are  adherent  to  the 
skin,  but  movable  on  the  deeper  structures.  They  are  smooth  and  often  flat  on  the 
surface,  and  mostly  soft  to  the  touch.  They  vary  in  colour  from  a  bluish-red  to 
a  brown-red,  the  variation  depending  upon  the  depth  in  the  cutis  at  which  they 
are  situated.  Occasionally  large  areas  of  skin  are  affected  with  a  difl'use  swelling, 
and  several  cases  have  been  described  in  which  the  face,  forehead,  cheeks,  lips, 
and  ears  have  been  implicated.  In  the  classical  case,  of  wliicli  there  is  a  moulage 
in  Finger's  clinic  in  Vienna,  the  face  is  so  involved  that  the  patient  looks  as  if  she 
were  sufiering  from  tlie  leontiasic  condition  to  be  met  with  in  leprosy. 

The  tumours  may  remain  unchanged  for  years,  or  some  may  spontaneously 
disappear,  or  the  disease  may  rapidly  spread  and  kill  the  patient.  The  blood- 
count  may  be  normal,  or  there  may  be  a  lymphocytosis. 

Histologically,  one  finds  in  the  cutis  a  collection  of  cells,  which  consists  entirely 
of  lymphocytes.  It  is  stated  that  a  space  is  always  left  free  between  the  tumour 
and  the  epidermis,  which  is  not  the  case  in  Mycosis  fungoides,  hence  a  ready  means 
of  distinguishing  the  two  conditions. 

The  statement  is  totally  incorrect,  since  not  infrequently  in  Leucaemia  cutis — ■ 
especially  in  the  diffuse  infiltrated  lesions — the  collection  of  lymphocytes  reaches 
up  to,  and  presses  upon,  the  epidermis  ;  while,  in  several  cases  of  Mycosis  fungoides, 
a  free  space  exists  between  the  epidermis  and  the  cellular  infiltration,  depending 
entirely  upon  whether  an  early  or  late  lesion  is  examined,  upon  whether  the  lesion 
is  small  or  large,  and  upon  the  area  through  which  the  section  is  made. 

Several  of  the  tumours  of  Leucaemia  cutis  have  been  known  to  ulcerate,  and 
in  this  fact  lies  the  close  resemblance  between  this  condition  and  Mycosis  fungoides. 

A  leucaemic  lesion  of  the  skin  may  have  a  green  colour,  and  so  be  a  chloroma, 
but  the  condition  is  extremely  rare.     The  starting  point  of  the  new  growth  may 

2  M  2 


546  BIOLOGY   OF   INFLAMMATION   AND   MALIGNANT  DISEASE. 

not  be  in  the  lymphocyte,  but  in  the  plasma  cell,  the  cell  to  which  it  gives  rise.  The 
same  occurs  in  epithelioma.  The  process  may  originate  in  the  basal  cell  layer, 
or  in  the  layers  above,  which  develop  therefrom. 


Aleucaemia  Cutis. 

If  the  process  is  a  malignant  one,  the  growth  will  consist  entirely  of  the  cell 
primarily  attacked,  i.e.,  a  Ijmiphosarcoma  will  consist  of  only  lymphocytes 
possessing  mahgnant  characters.  A  sarcoma  arising  in  plasma  cells  will  consist  of 
only  plasma  cells  possessing  mahgnant  characters.  Instead  of  either  of  these  cells, 
the  endothelial  cell  may  be  primarily  attacked,  the  growth  of  which  may  be  either 
innocent  or  mahgnant. 

As  a  plasma  cell  arises  from  a  lymphocyte,  any  new  growth  thereof  should  be 
considered  here. 

Plasmosarcomatosis  (Plate  52  (2)). — The  condition  appears  to  be  extra- 
ordinarily rare,  and,  as  I  have  had  a  case  under  my  care,  it  would  be  as  well  to 
publish  it  in  full." 

Case  84. — A  man,  aged  32  years,  came  up  for  advice,  complaining  of  an  ulcer  in 
the  middle  of  the  upper  third  of  the  thigh.  The  ulcer  was  hard,  crateriform,  and 
the  skin  for  some  distance  round  was  markedly  indurated. 

The  forerunner  of  the  ulcer  was  a  small  hard  and  painful  hunp,  which  made 
its  appearance  six  months  previously.  As  the  lump  began  to  soften  in  the  middle, 
it  was  incised,  but  only  a  very  small  quantity  of  pus  came  from  it.  From  this  tiaie 
onward,  the  ulcer  rapidly  increased  in  size.  When  I  first  saw  the  patient,  the  ulcer 
was  \\  in.  in  diameter,  bled  freely  on  touching  it,  and  was  extremely  hard.  The 
surrounding  skin  was  stretched,  of  a  brownish-red  colour,  indurated,  and  immov- 
able. The  inguinal  glands  on  the  affected  side  were  enlarged  and  hard.  The 
patient  had  never  had  a  venereal  disease. 

In  spite  of  all  treatment,  which  was  unavailing,  the  ulcer  readily  increased 
in  depth  and  size,  the  inguinal  glands  on  both  sides  became  affected,  and  the 
patient  died  six  months  later,  in  a  condition  of  cachexia.  Post-mortem  secondary 
growths  were  found  in  the  spleen,  in  the  kidneys,  in  the  mesenteric  glands,  and  in 
the  walls  of  the  small  intestine. 

A  microscopic  examination  of  the  margin  of  the  ulcer  showed  the  following 
characters  (Plate  52  (2))  :— 

The  epithelium  is  hypertrophied  and  acanthotic,  the  papillae  are  enlarged, 
otherwise  the  epidermis  is  normal.  The  corium  is  filled  with  new-formed  connective- 
tissue   cells   and   plasma   cells.     The   capillaries   are   dilated,   but   are    of    normal 


I 


ROLE    PLAYED    BY    LYiMPHOCYTE.  547 

structure.  Deeper  in  the  corium,  the  walls  of  the  blood  vessels  arc  h3'pertrophied 
and  infiltrated  with  lymphocytes. 

Arranged  perivascularly  are  numerous  plasma  cells,  which,  iu  some  places, 
can  be  clearly  seen  to  have  originated  from  lymphocytes,  which,  in  their  turn,  have 
arisen  from  the  endothelial  cells. 

Deeper  still  in  the  corium  or  subcutaneous  tissue,  a  mass  of  cells  is  to  be  seen, 
between  which  there  is  no  connective  tissue.  Each  cell  is  three  or  four  times  as 
large  as  a  normal  plasma  cell,  and  the  nucleus  takes  up  the  greater  part. 

The  protoplasm  stains  faintly  and  is  granular,  and,  in  many  of  the  cells,  the 
outline  of  the  protoplasm  is  broken,  so  that  the  granules  appear  to  be  extra- 
cellularly  situated. 

The  nucleus  stains  faintly,  contains  little  chromatin,  but  one  or  more  brightly 
staining  nucleoli. 

Some  cells  contain  two  or  three  nuclei,  each  of  which  may  contain  more  than 
one  nucleolus. 

Here  and  there,  bare  nuclei  are  to  be  seen,  owing  to  the  degeneration  of  the 
protoplasm  which  once  surrounded  them. 

The  nuclei  have  divided  neither  by  mitosis  nor  by  true  amitosis,  but  have 
been  merely  split  up  irregularly,  according  to  the  arrangement  of  the  existing 
chromatin  strands. 

In  the  margin  of  the  new  growth,  numerous  plasma  cells  are  to  be  seen,  and 
the  gradual  transition  from  these  plasma  cells  into  the  sarcoma  cells  is  in  several 
places  evident. 

To  a  similar  condition  the  terms  "  lymphosarcomatosis "  and  "  leucosar- 
comatosis  "  have  been  applied.  The  disease  may  start  as  an  ulcer,  with  intense 
brawny  induration  of  the  tissue  around,  as  in  the  case  described,  or  it  may  be  the 
end  of  many  of  the  cases  belonging  to  the  Mycosis  fungoides  group. 

The  so-called  Sarcomatosis  cutis  (Kaposi)  (one  type),  is  the  same  condition  as 
the  Leucaemia  cutis.  The  other  type  is  a  distinct  condition,  which  has  no  immediate 
relationship  to  the  lesions  under  discussion. 

The  Sarcomatosis  cutis  (Spiegler)  is  cjuite  another  condition,  and  is  identical 
with  the  so-called  sarcoid,  which  is  not  a  new  growth  at  all,  but  an  ordinary 
inflammatory  lesion,  due  to  the  tubercle  bacillus  or  its  toxine. 

Endothelial  lymjihocytoma. — Sibley  has  recently  had  a  case  of  what  one  may 
call  the  endotheUal  type  of  a  cutaneous  lymphocytoma.  I  have  been  able  to  make 
a  pathological  report  upon  this  case,  and,  with  Dr.  Sibley's  kind  permission,  I  am 
able  to  reproduce  it  here. 

Histology. ^k\t\:iO\\g\i   there    are    main   masses   of  cellular    infiltration,    which 


548  BIOLOGY   OF   INFLAMMATION    AND   MALIGNANT   DISEASE. 

are  more  or  less  circumscribed,  and  do  not  invade  tlie  subcutaneous  tissue,  the 
whole  of  the  corium  is  studded  with  a  cellular  infiltration  to  a  greater  or  to  a  less 
degree. 

In  the  periphery  of  the  main  masses,  what  at  once  strikes  the  eye  is  the  marked 
dilatation  of  the  capillaries  and  lymphatics,  the  perivascular  arrangement  of  the 
infiltration,  and  the  great  number  of  mast  cells.  In  some  sections  there  are  numerous 
eosinophile  cells.  If  the  vessels  and  lymphatics  are  more  closely  studied,  one  notices 
that  there  is  a  marked  endothelial  proliferation,  which,  in  some  places, 'is  sufficient 
to  block  the  lumen.  Some  of  the  endothehal  cells  have  extended  excentrically,  and 
here  the  main  increase  of  cells  is  made  up  of  connective-tissue  cells  and  lymphocytes. 
There  are  no  plasma  cells. 

The  main  masses  are  less  cellular,  owing  to  the  fact  that  several  of  the  cells  have 
degenerated,  and  that  the  cell  playing  the  most  part  in  the  infiltration  is  the  large, 
badly  staining  endothelial  cell. 

In  the  main  masses  there  are  not  many  lymphocytes,  and  no  plasma  cells  or 
mast  cells  ;  but  here  and  there,  where  a  few  endothelial  cells  have  coalesced,  typical 
giant  cells  are  to  be  seen.  In  the  immediate  periphery,  the  number  of  lymphocytes 
is  increased,  there  are  a  few  mast  cells,  no  plasma  cells,  but  a  very  marked  increase 
of  connective-tissue  cells.  Especially  noticeable  about  the  cellular  infiltration,  as 
a  whole,  is  the  poor  affinity  which  the  endothelial  cells  and  lymphocytes  show  for 
pyronin  and  methyl  green,  especially  for  the  former.  This  means  not  only  that 
the  protoplasm  of  the  cells  is  very  poor  in  hpoid-globulin,  and  therefore  markedly 
degenerate,  but  also  that  the  nucleic  acid  content  is  diminished,  which  renders 
the  cell  more  degenerate  still. 

Examining  the  cells  individually,  the  following  characters  are  to  be  noted  : — 

Endothelial  cells. — The  protoplasm  is  swollen,  stains  faintly,  and  is  sometimes 
granular.  In  a  few  of  the  cells,  embryo  lymphocytes  are  to  be  found,  but  they 
are  very  few  in  number,  and  not  pyroninophile.  On  the  other  hand,  they  show  a 
great  affinity  for  methyl  green,  with  which  they  stain  very  deeply.  Instead  of 
the  embryo  lymphocytes  being  well  formed,  their  nuclei  are  more  often  to  be  seen 
broken  up,  so  that  the  protoplasm  of  the  endothelial  cell  appears  to  be  crowded 
with  small  masses  which  stain  almost  black  with  methyl  green. 

The  nuclei  of  the  endothelial  cells  are  swollen,  many  cells  have  one  or  more 
nuclei,  and  the  nuclei  may  contain  one  or  more  nucleoli.  The  nucleoli  are  remark- 
able in  being  so  faintly  p^Toninophile. 

Lymphocytes. — Those  ahead}'  formed  stain  faintly  with  methyl  green,  and  are 
degenerated.  Here  and  there,  is  to  be  seen  a  feeble  attempt  to  form  plasma  cells, 
the  protoplasm  of  which  is  irregular,  and  only  stains  faintly  with  pjTonin.     A  few 


ROLE    PLAYED    BY    LYMPHOCYTE.  549 

embryo  lymphocytes  are  to  be  found,  but  it  is  an  exception  for  them  to  contain  a 
iipoid-iilobuUn  and  pyroninophile  protoplasm.  Most  of  the  embryo  lymphocytes 
are  merely  masses  of  nuclcin. 

Lymphatic  gland  from  axilla. — The  gland  is  a  very  small  one,  but  practically 
the  whole  of  its  structure  is  altered.  There  is  very  little  cortex,  as  most  of  the  gland 
consists  of  abnormal  follicular  tissue.  The  number  of  lymphocytes  is  diminished, 
while  the  endothelial  cells  are  very  much  increased.  In  the  gland  section  there 
are  a  few  plasma  cells,  and  more  normal  embrj'o  lymphocytes.  The  endothelial 
cells  resemble  those  already  described  in  the  skin  section. 

The  sections  of  both  the  skin  and  the  lymphatic  gland  resemb'e  Plate  52  (1), 
but  with  certain  differences. 

The  endothelial  cells  are  the  cells  attacked,  consequently  there  is  a  great  multi- 
plication of  them,  and,  owing  to  their  great  desire  to  increase,  as  shown  by  their  being 
nmltiimcleated,  they  are  unable  to  generate  lymphocytes.  The  few  lymphocytes 
formed  will  also  be  degenerated,  hence  they  lack  their  characteristic  lipoid-globulin 
envelope,  and  consist  of  irregular  masses  of  nuclein. 

The  cHnical  history  of  this  case  is  interesting,  as  it  throws  light  upon  other 
cases  I  have  seen,  which  have  been  less  severe,  and  to  which  a  name  has  never 
yet  been  given. 

Case  85. — The  patient^*  was  a  boy,  aged  1 6,  whc-  is  stated  to  have  had  an 
eruption  for  eight  years.  The  patient  had  a  diffuse  papular  eruption  with  a  marked 
pigmentation  of  the  skin,  and  a  general  adenitis.  In  many  places  the  papules  had 
coalesced,  and  all  that  could  be  said  of  the  wide  area  of  skin  affected,  notably  on 
the  upper  part  of  the  thighs,  was  that  the  skin  presented  a  condition  of  chronic 
dermatitis.  The  rash  was  irritable.  The  patient  was  hoarse,  he  ran  an  evening 
temperature,  his  blood  count  was  normal  at  first,  but  it  later  developed  a  leucaemie 
picture  (eosinophilia).     Otherwise  nothing  else  abnormal  was  found. 

I  have  seen,  as  just  stated,  similar  although  less  severe  cases,  in  which  the 
whole  skin  was  in  a  condition  of  chronic  dermatitis,  with  what  might  be  called 
granulation  tumoiu's  scattered  over  it.  Sibley's  case  had,  just  prior  to  examination, 
gone  through  a  severe  attack  of  impetigo,  and  I  have  noticed,  in  some  of  the  cases 
just  referred  to,  that  recurrent  attacks  of  a  generalised  pyogenic  infection  are  not 
at  all  uncommon.  The  itching  is  always  intense  ;  all  the  lymphatic  glands  of  the 
body  swell  in  time,  but  those  fii-st  to  become  enlarged  are  the  femoral  and  inguinal 
sets.  The  blood  picture  is  at  first  normal,  but  later  it  may  show  a  pronounced 
eosinophilia ;  the  eosinophiles,  being  both  absolutely  and  relatively  increased. 
The  disease  is  essentially  chronic,  but  ultimately  fatal,  and  all  the  cases  I  have 
seen,  five  in  all,  have  been  Polish  Jews.     I  have  studied  the  histology  of  the  skin 


550  BIOLOGY   OF   INFLAMMATION   AND    MALIGNANT   DISEASE. 

and  lymphatic  glands  in  these  cases,  and  not  only  are  no  two  exactly  aUke,  but 
also  the  histology  varies  in  the  same  case,  according  to  the  length  of  time  during 
which  the  various  lesions  have  been  present. 

The  cellular  infiltration  may  be  at  one  time  lymphocytic,  at  another  it  may 
consist  mainly  of  plasma  cells,  and  at  another  of  endothelial  cells,  as  in  Sibley's 
case.  The  characters  of  the  cell  affected  may  vary ;  for  instance,  the  protoplasm 
of  the  plasma  cells  may  be  broken  up  {vide  Plate  51  (1)) ;  the  plasma  cells  or  the 
endothehal  cells  may  exhibit  pronounced  nuclear  or  even  nucleolar  activity.  Hence 
in  these  cases  alone,  the  various  Hnks  of  my  lymphocytic  chain  may  be  met  with. 

This  case,  from  its  histological  features,  would  probably  have  been  called 
lymphogranulomatosis  on  the  Continent,  and  lymphadenoma  or  Hodgkin's  disease 
affecting  the  skin  in  this  country.  There  was  a  leucocytosis  of  over  25.000,  the 
feature  of  Avhich,  was  a  very  pronounced  eosinophilia.  Strictly  speaking,  the 
blood  picture  is  leucaemic.  but  as  the  usual  meaning  of  the  word  is  so  restricted, 
it  has  to  receive  the  appellation — aleucaemic. 

Intermediary  Aleucaemia  Cutis. 
Mycosis  Fungoides. 

As  everyone  is  aware,  Mycosis  fungoides  is  regarded  by  some  observers  as 
a  form  of  sarcoma,  and  by  others  as  a  form  of  leucaemia,  or  rather  pseudo- 
leucaemia.  The  latest  opinion  is  that  Mycosis  fungoides  lesions  are  made  up 
of  pure  granulation  tissue,  and  have  no  relationship  to  either  sarcoma  or  leucaemia  ; 
in  other  words,  that  it  is  a  disease  sui  generis.  One  of  the  reasons  for  classifying 
the  disease  among  the  sarcomata  was  the  fact  that  lesions  similar  to  those  occurring 
in  the  skin  were  also  to  be  found  in  the  internal  organs. 

Paltauf  and  v.  Zumbusch*  have  recently  described  two  cases  of  Mycosis 
futigoides,  in  which  lesions  were  found  ■post-mortem  in  the  internal  viscera. 

In  the  one  case  there  was  an  infiltration  of  the  pleura,  nodules  in  the  lungs, 
and  infiltration  with  ulceration  of  the  walls  of  the  stomach.  The  coloured  plates 
illustrating  the  article  depict  the  le.sions  of  the  viscera  as  yellow  nodules  with  a 
marked  red  inflammatory  circumference,  and  they  do  not  suggest  metastases  of  a 
primary  malignant  growth. 

Microscopically,  these  lesions  were  made  up  of  granulation  tissue,  which  was 
especially  rich  in  plasma  cells,  resembhng  the  cutaneous  lesions.  In  both  cases, 
necrosis  was  to  be  met  with. 

Unfortunately,  no  detailed  description  of  the  morphology  of  the  plasma  cells 
is  given.  In  the  other  case,  nodules  were  to  be  found  in  the  lungs,  liver,  and  spleen, 
and  macroscopically  and  microscopically  they  were  identical   with  the  cutaneous 


ROLE   PLAYED   BY   LYMPHOCYTE.  551 

lesions,  having  the  characteristics  of  an  inflammatory  ratiier  than  of  a  malignant 
growth. 

On  the  other  hand,  cases  have  been  described  in  wiiicii  the  lesions  of  the  internal 
viscera  were  sharply'  circumscribed,  non-inflammatory — in  short,  having  all  the 
phenomena  of  secondary  malignant  growths.  Tiic  cases  were  described  some 
time  ago,  and  the  histology  of  these  so-called  metastatic  lesions  was  not  adequately 
worked  out.  It  is  possible  that  some  of  the  cases  described,  in  which  secondary 
malignant  growths  have  been  found,  have  been  cases  in  which  a  primary  malignant 
growth  existed  mdependently  of  the  Mycosis fungoides. 

Adamson  recently  had  a  case  of  Mycosis  fungoides  in  a  woman,  and  it  was 
marked  by  generalised  pigmentation,  in  which — post-moHem — a  secondary  growth 
was  found  in  the  liver.  The  secondary  growth  was  sharply  circumscribed,  non- 
inflammatory, about  the  size  of  a  filbert,  and  it  was  deeply  pigmented  in  parts. 
Histologically  it  was  clearly  a  metastatic  melanotic  malignant  epithelioma.  Some 
years  previously,  the  left  eye  had  been  removed,  possibly  for  a  growth,  but  no 
further  details  on  this  point  are  at  present  obtainable.  In  some  of  the  cutaneous 
mycosis  lesions,  removed  post-mortem,  metastatic  malignant  epitheliomatous 
deposits  are  to  be  seen. 

The  reason  for  classifying  Mycosis  fungoides  among  the  leucaemias  is  due  to 
the  fact,  that  the  statement  has  crept  into  text-books,  that  the  disease  is  sometimes 
associated  with  a  blood-count,  suggestive  of  lymphatic  leucaemia. 

It  is  extremely  doubtful  whether  the  blood-count  is  often  altered  in  Mycosis 
fungoides,  except  beyond  an  increase  of  eosinophiles  in  some  cases,  and  poly- 
morphonuclear leucocytes  in  others,  which  are  accompanied  by  necroses.  Person- 
ally, I  have  not  come  across  a  case  with  a  pronounced  mononuclear  leucoc)'tosis, 
but  a  small  increase  in. the  large  mononuclears  may  sometimes  be  met  with. 

As  to  whether  Mycosis  fungoides  should  be  classed  with  the  pseudo-leucaemias, 
depends  upon  what  one  recognises  as  pseudo-leucaemia.  The  best  known  example 
of  a  pseudo-leucaemic  condition  is  what  we,  in  England,  call  Hodgkiu's  disease.  On 
the  Continent  the  same  condition  usually  goes  by  the  name  of  lymphogranulomatosis. 
Many  observers  hold  that  Mycosis  fungoides  and  lymphogranulomatosis  are  one 
and  the  same  condition,  affecting  different  parts  of  the  body. 

On  the  other  hand,  other  observers  maintain  that  they  have  nothing  in 
common,  although  the  reasons  given  for  the  statement  are  far  from  convincing. 
Their  chief  reason  for  separating  the  two  conditions  is,  that  IjTnphogranulomatosis 
is  preceded  by  urticarial  and  prurigo-like  lesions  of  the  skin,  with  occasionally  a 
widespread  erythrodermia,  while  Mijcosis  fungoides  is  usually  preceded  by  an 
eczema  or  a  psoriasis. 


552  BIOLOGY   OF   INFLAMMATION   AND   MALIGNANT   DISEASE. 

As  far  as  my  limited  experience  goes,  in  cases  of  so-called  pseudoleucaemia 
with  skin  lesions  resembling  urticaria  and  prurigo,  the  skin  lesions  either  appear 
some  time  after  one  or  more  sets  of  lymphatic  glands  have  become  enlarged,  or  they 
appear  before  there  is  any  enlargement  of  the  palpable  lymphatic  glands.  The 
point  I  wish  to  bring  out  is,  not  whether  the  skin  lesions  precede  or  succeed 
lymphatic  gland  enlargement,  but  that  in  the  majority  of  the  cases  the  skin  lesions 
do  not  alter.  Some  of  the  prurigo  papules  may  increase  in  size,  but  it  seems 
doubtful  whether  they  ever  give  rise  to  such  nodules  as  are  seen  in  Mycosis 
fungoides.  Skin  lesions  such  as  just  described,  I  take  to  be  entirely  secondary  to 
the  main  condition  and  not  homologous  parts  of  it. 

Some  of  these  cases  may  run  an  extremely  rapid  course,  death  ensuing  in  a 
few  weeks,  but  more  often  the  disease  lasts  over  many  years. 

Whether  the  course  is  rapid  or  slow,  the  blood-count  usually  remains  the 
same.  There  is  generally  a  diminution  of  lymphocytes,  an  increase  of  eosinophiles 
often  to  .30  per  cent.,  and  an  increase  of  polymorphonuclears,  the  last  being 
dependent  upon  the  secondary  infection  which  is  liable  to  result  from  the  continued 
scratching.     On  the  other  hand,  the  blood-count  may  remain  normal  to  the  end. 

The  cases  exhibiting  erythrodermia  may  be  divided  into  two  classes  :  those 
in  which  the  erythrodermia  is  widespread  and  often  sufficient  to  produce  total 
alopecia,  and  those  in  which  the  erythrodermia  is  localised  to  one  or  more  patches. 
In  both  cases,  the  erythrodermia  may  disappear  before  any  tumour  formation  is 
seen,  leaving  either  no  trace  behind  it,  or,  more  often,  a  marked  pigmentation  ;  or 
the  tumour  formation,  especially  in  the  localised  cases,  may  appear  in  the  centre 
of  the  patches  of  erythrodermia. 

The  tumours  may  ulcerate,  a  process  which  usually  results  in  their  spontaneous 
cure — not  in  a  cure  of  the  disease,  because  fresh  patches  of  erythrodermia,  with 
ultimate  tumour  formation,  will  appear  elsewhere.  I  have  had  one  singular  case 
under  my  care,  an  exact  replica  of  which  I  have  never  seen  described. 

Case  86. — A  man,  aged  -17  years,  having  had  syphiUs  over  tw^enty  years  before, 
sought  advice  for  a  skin  lesion  he  had  had  for  the  last  three  years. 

The  patient  had  a  rash  which  extended  over  the  upper  half  of  the  left  side  of 
the  chest,  the  left  shoulder,  and  down  the  left  arm  to  about  the  lower  third.  The 
rash  was  typical  of  Dermatitis  atrophicans,  the  skin  rolled  and  looked  thin,  like 
cigarette  paper,  and  the  vessels  were  clearly  discernible  underneath.  The  periphery 
of  the  lesion  simulated  exactly  the  localised  patches  of  erythrodermia,  which 
precede  the  condition  called  Lym'pliogranuloinatosis  cutis.  The  itching  was  intense, 
and  the  skin  trouble  was  undoubtedly  spreading.  On  the  arm,  where  the  skin 
had  not  become  atrophic,  was  a  very  slowly  spreading  ulcer,  which  simulated  closely 


Plate  51. 


Section  of  a  lymphatic  gland  stained  with  pyronin  and  methyl  green,  from 
a  case  of  intermediary  l3miphatio  aleucsemie  lymphooytoma.  The  patient 
had  a  wide-s])read  prurigo-likc  exanthem.  The  blood-coimt  showed  a  shght 
diminution  of  lymphocytes,  and  a  slight  increase  of  polymorphonuclear  leuco- 
cytes and  eosinophiles.  The  characteristic  feature  of  the  section  is  the 
manner  in  which  the  protoplasm  of  the  plasma  cells  has  broken  up,  into 
pyioninopliile  amorphous  masses. 


This  section  is  from  a  case  of  intermediary  aleucaemic  cutaneous  lympho- 
oytoma, near  the  malignant  end  of  the  chain.  The  patient  was  a  man,  aged 
50  years,  who  had  patches  of  erythrodermia,  in  the  centre  of  which  were 
several  nodules,  some  of  which  had  ulcerated.  The  nodules  and  ulcers  after 
a  time  disappeared  spontaneously.  Twenty-five  years  previously  he  had  had 
syphilis,  and  at  time  of  examination  the  Wassermann  reaction  was  strongly 
positive.  His  mother  died,  aged  78  years,  and  his  father,  aged  82  years,  was 
still  alive.  Patient  was  steadily  losing  weight,  and  all  the  hair  on  the  body 
was  rapidly  coming  off.  Occasionally  the  itching  was  very  severe.  Glandular 
enlargement  was  very  marked.  The  blood  examination  showed  an  eosinophilia 
and  a  slight  increase  of  the  large  mononuclears.  Histologically,  the  points 
to  be  noticed  are,  the  granulation  and  breaking  away  of  the  protoplasm  of 
the  plasma  cells,  an  increase  in  the  size  and  number  of  the  nuclei  of  the 
plasma  cells,  a  diminution  in  staining  properties  of  their  chromatin,  and  an 
increase  in  size  and  number  of  the  nucleoli. 


3. 

Section  of  a  IjTnphatio  gland  from  a  rapid,  fatally  terminating  case  of 
intei-mediary  lymphatic  aleuoaemic  lymphocytoma.  The  patient  had  an  acute 
universal  prurigo-like  exanthem.  The  points  to  be  noted  are,  that  the 
protoplasm  of  some  of  the  plasma  cells  has  broken  up,  the  nuclei  of  most  of 
the  plasma  cells  have  increased  in  size,  some  have  divided,  and  man}' 
contain  more  than  one  nucleolus,  and  some  of  the  nuclei  of  the  plasma  cells 
and  lymphocytes  have  been  displaced  by  a  strongly  pyroninophile  body — 
the  nucleolus,  which  has  increased  tremendously  in  size.  Elsewhere  in  the 
section,  nucleoli  are  to  be  seen  forming  cells  of  their  own  and  dividing, 
behaving  like  the  pseudo-parasites  of  malignant  epithelioma. 


Facing  p.  552. 


je  ai'Aj'l 


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Plate  51. 


ROLE    PLAYED    BY   LYMPHOCYTE.  553 

a  rodent  ulcer.     All  treatment  was  unavailing.     The  patient  was  not  clear  as  to 
whether  the  ulcer  had  been  preceded  by  a  swelling  in  the  skin  or  not. 

The  tumours  which  form  on  the  patches  of  erythrodormia  are  clinically 
indistinguishable  from  those  which  succeed  an  eczematous  or  psoriatic  condition, 
or  from  those  which  arise  independently  of  an}'  preceding  dermatitis  {Mycosis 
d'emblee). 

Therefore,  clinically  it  would  appear  that  there  is  no  difference  between  Mycosis 
fwngoides  and  Lymjihogranuhmatosis  cutis.  Broadly  speaking,  when  a  histological 
examination  of  any  of  the  afore-mentioned  cases  is  made,  one  may  say  that  scarcely 
any  two  are  alike.  They  all  have  a  feature  in  common,  viz..  that  the  predominating 
cell  of  the  infiltration  is  a  lymphoc)i:e.  The  varied  microscopic  pictures  obtained, 
are  accounted  for  by  the  presence  or  ahnost  total  absence  of  plasma  cells  in  some 
cases,  upon  the  presence  or  absence  of  the  forerunners  of  lymphocytes,  and  upon 
the  variation  in  the  number  of  polymorphonuclear  leucocytes,  mast  cells  and  eosino- 
philes.  In  some  cases,  the  tumour  may  be  made  up  almost  entirely  of  plasma  cells  ; 
they  ma  V  be  normal,  the  protoplasm  maybe  broken  up  in  the  cells  of  which  the  nucleus 
remains  unchanged  (Plate  51  (1)) ;  the  protoplasm  may  be  granular  (Plate  .51  (2)),  in 
the  cells  of  which  the  nucleus  is  either  increased  in  size  or  there  is  more  than  one, 
and  the  nucleoli  are  also  increased  both  in  size  and  numerically  (Plate  52  (2)) ;  or 
the  protoplasm  may  have  practically  vanished,  also  the  nucleus,  the  nucleolus 
only  being  left  behind,  which  divides  and  subdivides,  or,  in  other  words,  behaves 
pseudo-parasitically  (Plate  51  (3)),  a  phenomenon  I  have  de.scribed  as  occurring  in 
the  epitheUal  cells  of  mahgnant  epitheliomata.  In  other  cases,  tliere  are  no  plasma 
cells  at  all,  the  infiltration  being  made  up  of  small  and  large  lymphocytes.  In 
such  cases,  it  is  usual  to  find  many  endothelial  cells  with  embryo  Innphocytes  in 
their  protoplasm.  In  other  .such  cases,  there  may  be  numerous  large  cells  containing 
one  or  several  nuclei  in  their  feebly-staining  protoplasm.  Sternberg'  first  called 
attention  to  these  cells,  and  held  them  for  characteristic  of  lymphogranulomatosis. 
These  large  cells  are  mostly  round,  and  contain,  as  ju.st  stated,  one  nucleus  or  more. 
The  nucleus  or  nuclei  may  be  centrally  or  peripherally  situated,  they  vary  in  shape, 
contain  httle  chromatic  substance,  but  one  or  more  deeply-.staining  nucleoH. 

The  greatest  difference  of  opinion  prevails  as  to  the  origin  of  these  cells. 
Personally,  I  think  they  are  the  endothelial  cells  of  the  local  lymph  vessels,  which 
have  been  unable  to  generate  lymphocytes,  and  that  they  are  identical  with  the 
large  cells  depicted  in  the  section  of  a  lymphatic  gland  from  the  neck  of  a  rat  which 
died  of  trypanosomiasis  (Plate  50  (2)).  In  all  cases,  there  is  a  greater  or  less 
proliferation  of  the  fixed  connective-tissue  cells,  and  it  occurs  whenever  there  is  an 
inflammatory  infiltration  of  the  skin,  and  is  therefore  in  no  wise  specific. 


554  BIOLOGY   OF   INFLAMMATION   AND   MALIGNANT  DISEASE. 

In  other  cases  (Plate  52  (1)),  embryonic  lymphocytes  predominate,  and  they 
behave  in  a  manner  that  has  never  hitherto  been  described.  The  parent  endothelial 
cells  of  these  embryonic  lymphoc3rtes  are,  owing  to  degeneration,  difficult  to  see. 
These  embryonic  lymphocytes  vary  in  size  and  shape,  but  all  stain  homogeneously 
and  very  deeply  with  methyl  green,  polychrome  methylene  blue,  etc.  These 
darkly  staining  masses  which  consist  of  nuclein,  which  has  not  yet  become  differen- 
tiated into  chromatin  threads  and  dots,  are  sometimes  seen  to  be  lying  in  a  mass  of 
protoplasm  which  takes  the  pyronin  stain.  Either  very  little  protoplasm  is  seen 
or  a  considerable  amount,  and,  in  the  latter  instance,  one  or  more  strongly  pyronino- 
phile  bodies  are  generally  visible,  one  of  which  lies  invariably  at  one  pole  of  the 
nucleus.  These  pvi'oninophile  bodies  are  presumably  nucleoli.  What  has  just  been 
stated  is  well  depicted  in  Plate  52  (1),  and  one  cannot  help  noticing  the  close 
similarity  between  the  various  stages  met  with  in  the  lymphocyte  and  the  epithelial 
cell  when  pseudo-parasitism  occurs. 

The  section  is  taken  from  a  case  of  Mycosis  fungoides  and  the  interpretation 
I  would  put  upon  it  is  as  follows  : — 

The  attacking  force  strikes  the  lymphocytes  just  after  they  have  been  expelled 
from  the  endothelial  cells,  therefore  the  resistance  will  be  shown  by  the  embryonic 
lymphocytes  and  the  endothelial  cells. 

In  this  case,  although  numerous  endothelial  cells  are  to  be  seen  in  the  section, 
the  brunt  of  the  resistance  is  being  borne  by  the  young  lymphocytes,  a  point  in 
favour  of  regarding  the  case  as  being  nearer  the  malignant  than  the  innocent  end 
of  the  chain. 

The  embryo  lymphocytes  divide  and  subdivide  amitotically,  which  accounts 
for  the  great  difference  in  size  of  the  nuclein  masses  ;  others  develop  a  large  area 
of  protoplasm  in  their  abortive  attempt  to  form  plasma  cells  ;  in  some  of  the  latter, 
and  in  some  of  the  non-protoplasmic  embryo  lymphocytes,  the  nucleolus  is  beginning 
to  behave  as  a  pseudo-parasite. 

Some  of  the  larger  young  lymphocytes  have  broken  up  into  several  small 
nuclein  masses,  possibly  with  the  hope  of  forming  several  distinct  lymphocytes, 
and  in  these  cells  the  nucleolus  is  also  active. 

The  most  interesting  point  about  this  case,  which  was  under  Dr.  Adamson's 
care,  is  that,  when  the  case  was  first  seen,  the  lesions  were  rapidly  getting  better, 
and  microscopically  were  typical  plasmomata.  When  the  condition  recurred  and 
ended  fatally,  practically  no  plasma  cells  at  all  were  to  be  found  in  the  sections. 
The  case  had,  in  short,  become  more  malignant.  It  is  frequently  to  be  noticed 
that  the  histology  of  a  recurrent  mycosis  lesion  differs  from  that  of  one  of  the 
primary  lesions. 


tf/i 


Plate  52. 


1. 


A  section  from  a  recurrent  case  of  intermediary  cutaneous  aleucaemic 
lymphocytoraa  after  X-rays.  Before  treatment,  the  lesions  were  histologically 
true  plasmomata.  Now,  several  endothelial  cells  are  to  be  seen,  some  of 
which  have  given,  and  are  giving  rise  to  lymphocytes.  The  embryo  lympho- 
cytes instead  of  forming  adult  lymphocytes  and  plasma  cells,  are  undergoing 
multiple  division,  and  some  of  them  have  formed  a  large  area  of  protoplasm. 
In  a  few  of  these,  the  nucleolus  is  active. 


Is  a  section  from  a  sarcomatous  ulcer,  which  arose  from  plasma  cells. 
The  points  to  be  noted  are,  the  granulation  and  disappearance  of  the  proto- 
plasm of  the  plasma  or  sarcoma  cells,  the  large  size  and  number  of  the  nuclei, 
the  feeble  staining  properties  of  the  chromatin,  and  the  increase  in  size  and 
number  of  the  nucleoli. 


,,    .  --.  1  PX^TH  52. 


.openeo\isl  ,• 


more  st- 


'    .     !  rielp  no  do,-!e 

mphocvte  &■  .1 

..,.f<.m/l  o^nJi.i'i  ■idT    f.av  iiififfdvl  o,1  -iiiiT  gnivig  318  bflc  ,n9Yig  evjsd  doidw 
-.r.iiik{uiozi.\  to  ii'jiii  ygijjl  fi  bom-iot  'j/'iii  nigrfJ  lo  amoa  biiB '.'nowivib  elqil;;     ' 


.<\i- '_<  Krf\>.rAii    inoTi    'Kinji  [ir^inv/  ,r»-i!U    -u>Mjiii'M.'iij-.     t,    ui'^ii   lU-'  ' -'o-'   ^    ^i 
oJoiq  adl  io  soxuruisqqAeib  bo*  noLlfik/n«-ig  eiU  ^th  titiioiii^l.f^  (sftaioqifntftiit  riid 
/ijloirn  idi  \o  ladfuiiii  bos  asia  agiel  oilJ  .alloo  sfliooifiB  lo  Btneslq  oril  5o  ineBlq 

.iifi -ivTv  rii    ivmiTiiii    5irU    hrij!  .fiil);i!!<jirio  od}   }o  Byij'i'xioiir  'ju'iii/ijc. 'jl-^ o-'l  eill 


luleolus 


ider  Dr. 


requently  to  d 

differs  from  that  of.  one  of  the 

.tec  .It  v"""^ 


^-i^..^/ 


Plate  52. 


ROLE    PLAYED    BY    LY'MPHOCYTE.  555 

The  histological  characters  of  the  recurrent  lesions  are  more  akin  to  those  to 
be  met  with  iu  sarcomata  than  in  pure  inflammatory  lesions,  and  since,  as  it  seems 
to  me  that  death  ensues  quicker  after  X-rays  than  would  otherwise  have  been  the 
case,  the  opinion  is  suggested  that  X-rays  stimulate  the  tendency  which  the  cells 
already  possess  of  developing  malignant  features.  For  some  interesting  work  on 
the  action  of  X-rays  on  the  cells  in  the  spleen  the  reader  must  be  referred  to  Ziegler's 
book,^^  in  which  several  points  are  brought  forward,  which  tally  with  what  I  have 
just  said. 

The  number  of  polymorphonuclears  present  is  regulated  by  the  amount  of 
secondary  infection,  and  by  the  fact  whether  necrosis  is  going  to  supervene  or  not. 
The  number  of  mast  cells  present,  depends  upon  the  amount  of  pigmentation.  The 
number  of  eosinophiles  present  varies  somewhat,  but  their  common  appearance, 
often  in  very  large  numbers,  suggests  a  specificity  of  some  kind. 

Great  as  the  variation  in  the  histological  changes  at  first  sight  appears  to  be, 
on  a  deeper  insight  the  difference  becomes  more  apparent  than  real.  The  hiupho- 
cyte  is  the  cell  attacked,  but  it  depends  upon  the  degree  of  the  attacking  force,  as 
to  whether  the  response  will  come  iu  the  form  of  a  plasma  cell,  a  lymphocyte,  an 
endothelial  cell  forming  lymphocytes,  or  an  endothelial  cell  incapable  of  forming 
Ijanphocytes.  The  cause  of  the  condition,  in  the  first  instance,  is  one  which  causes 
inflanimatiou  analogous  to  either  syphilis  or  to  tubercle,  in  that  the  lymphocyte, 
and  not  the  polymorphonuclear  leucocj-te,  responds. 

Should  the  attack  not  be  too  severe,  the  lymphocytes  will  form  plasma  cells, 
by  which  process  their  protective  capacity  is  increased.  Should  the  attack  still 
persist,  or  should  it  become  more  vigorous  while  a  plasmoma  exists,  the  plasma 
cells  constituting  it  will  increase  their  resistance,  and  this  they  can  do  by  breaking 
up  their  protoplasm,  which  increases  the  area  over  which  the  fennent  action  is 
spread  ;  or  the  protoplasm  fails,  when  the  nucleus  will  divide  and  subdivide,  with 
the  hope  of  forming  more  ;  and,  lastly,  the  nucleolus  will  do  its  best  by  behaving 
in  the  same  manner.  Should  the  attack  be  primarily  severer,  before  the  lymphocj'tes 
have  had  tune  to  form  plasma  cells,  the  increased  resistance  which  may  be  required 
\vill  be  thrown  upon  their  forerunners  or  the  endothelial  cells,  which  will  do  their' 
utmost  to  turn  out  the  greatest  quantity  of  l\Tnphocytes  possible.  Should  the 
resistance  required  be  greater  still,  the  endothelial  cells  will  attempt  to  divide  and 
subdivide,  so  that  each  resulting  endotheUal  cell  could  form  lymphocytes  inde- 
pendently ;  hence  the  appearance,  in  some  cases,  of  multi-nucleated  large  cells. 
Therefore,  cHnically  and  histologically,  Lijmjphodermia  pernidosa,  LytnpJwgranulo- 
matosis  cutis,  and  Mycosis  fungoides  are,  in  my  opinion,  names  for  different  stages 
of  the  same  condition. 


556  BIOLOGY   OP   INFLAMMATION   AND    MALIGNANT   DISEASE. 

Histological  changes  such  as  I  have  just  described,  which  are  depicted  in  Plates 
51  (1,  2,  3)  and  52  (1,  2),  are  also  to  be  met  with  in  the  lymphatic  glands  removed 
from  cases  with  cutaneous  lesions,  and  in  those  removed  from  cases  of  so-called 
Hodgkin's  disease.  Therefore,  it  would  appear  that  the  disease  may  start  either 
primarily  in  the  glands  or  in  the  skin. 

The  presence  or  absence  of  itching,  upon  which  observers  lay  so  much  stress, 
as  serving  to  distinguish  lymphogranulomatosis  from  Mycosis  fungoides,  must 
surely  be  a  slender  reed  to  lean  upon,  since  in  both  conditions  there  may,  or  may 
not,  be  pruritus.  Pruritus  is,  after  all,  more  an  idiosyncrasy  of  the  patient  than 
of  the  disease,  and  no  one  would  hesitate  to  diagnose  a  typical  case  of  Lichen  planus 
as  such,  simply  because  there  was  no  itching.  The  glandular  enlargement  is  said 
to  be  more  marked  in  cases  of  lymphogranulomatosis  than  in  cases  of  Mijcbsis 
fungoides.  First,  the  glandular  enlargement,  as  described  clinically,  will  only 
affect  those  glands  which  can  be  felt.  I  mention  this,  since  the  post-mortem 
examination  has  occasionally  revealed  an  enormous  enlargement  of  only  the  glands 
lying  deep  in  the  chest  and  abdomen.  Secondly,  a  ratio  exists  between  the 
enlargement  and  rate  of  increase  in  size  of  the  lymphatic  glands,  and  the  severity 
of  the  attacking  force ;  that  is  to  say,  that  in  those  cases  in  which  the  glandular 
enlargement  is  greatest,  one  would  meet  with  the  greatest  number  of  non-lympho- 
cytic-containing  endothelial  cells.  The  very  rare  condition,  mycotic  erythrodermia, 
which  has  been  described  by  Besnier,  Vidal,  Hallopeau,  and  others,  must  be  included 
in  the  group  under  discussion. 

According  to  the  authors  above  mentioned,  the  disease  is  characterised  by  a 
universal  redness  of  the  skin,  with  tumour  formation  ;  the  itching  is  intense  ;  there 
is  marked  lymphatic  gland  enlargement,  with  accompanying  swelhng  of  the  liver 
and  spleen.  In  most  cases,  after  two  or  three  years  the  disease  terminates  fatally. 
Aindt^,  in  a  recent  article,  attempts  to  draw  a  sharp  distinction  between  lympho- 
granulomatosis and  Mycosis-  fungoides,  and  he  would  even  assign  to  the  French 
mycotic  erythrodermia  a  distinct  position.  The  case  of  lymphogranulomatosis 
described  by  Arndt  had  remittent  fever  and  progressive  cachexia,  which  are 
not  usual  accompanying  signs  of  Mycosis  fungoides,  as  the  author  points 
out.  Histologically,  according  to  Arndt,  the  differential  diagnosis  rests  upon  the 
number  of  the  large  cells  which  are  to  be  found  containing  one  or  more  nuclei ;  if 
there  are  many,  the  case  is  one  of  lymphogranulomatosis  ;  if  few,  or  if  they  are 
absent,  then  the  case  is  one  of  3Iycosis  fungoides. 

Until  the  causes  of  Mycosis  fungoides  and  lymphogranulomatosis  have  been 
found,  we  shall  not  be  in  a  position  to  state  with  certainty  whether  they  are  distinct 
diseases,  or  only  different  phases  of  the  same  disease. 


ROLE    PLAYED    BY   LYiMPHOCYTE.  557 

Concerning  the  aetiology  of  Mycosis  fungoides,  nothing  vpiy  definite  is  known, 
but  in  some  cases  of  lymphogranulomatosis,  acid-fast.  Gram  jDositive  bacilli  have 
been  found  (Arndt).  Morphologically,  the  baciUi  resemble  tubercle  bacilli,  but 
whether  the  lesion  is  a  tuberculous  one,  or  whether  tubercle  has  supervened,  or 
whether  the  acid-fast  bacilli  belong  to  another  species,  are  problems  which  remain 
still  to  be  solved. 

Cases  of  Hodgkin's  disease  have  been  described,  in  which  acid-fast  bacilli  have 
been  found,  and  some  observers  have  also  found  what  the}-  term  the  coccoid  form 
of  the  tubercle  bacillus,  which  is  demonstrated  by  Much's  method  of  prolonged 
staining  with  gentian  violet. 

Owing  to  the  discovery  of  acid-fast  bacilli  in  both  Hodgkin's  disease  and 
iymphogranuloiiiatosis,  many  observers  hold  that  the  two  diseases  are  identical, 
but  that  one  form  mainly  affects  the  glands,  while  the  other  form  chiefly  affects  the 
skin  ;  also  that  both  conditions  have  a  close  connection  with  tuberculosis.  Ziegler* 
and  many  others  maintain  that  Hodgkin's  disease  and  lymphogranulomatosis  are 
similar  conditions,  but  hold  that  Mycosis  fungoides  should  also  be  included 
therewith. 

Owing  to  the  similar  clinical  picture,  and  to  the  fact  that  no  two  cases  of 
Hodgkin's  disease  and  lymphogranulomatosis  or  Mycosis  fungoides  are  histologically 
the  same,  and  as,  moreover,  the  aetiology  of  both  diseases  is  unknown,  in  my 
opinion  it  would  be  preferable  to  class  them  as  links  in  a  chain,  for  which  I  have 
proposed  the  name  of  aleucaemic-lymphocytoma. 

The  Mycosis  fungoides  would  come  nearer  to  the  inflammatory  end  of  the 
chain,  while  lymphogranulomatosis  would  approxunate  to  the  malignant  end. 
Owing  to  the  fact  that  most  of  these  conditions  primarily  begin  as  inflammatory 
lesions,  the  cells  constituting  them  not  differing  from  those  met  in  ordinary  inflam- 
mation, it  is  impossible  to  diagnose  a  premycotic  condition,  from  a  histological 
examination  only. 

It  is  interesting  to  inquire  a  little  further  into  the  aetiology  of  this  intermediary 
group.  The  only  satisfactory  evidence,  so  far  forthcoming,  is  that  acid-fast  bacilli 
have  been  found,  which  suggests  a  causal  relationship  to  tuberculosis.  Tuberculous 
lesions,  at  any  rate  in  the  skin,  are  mostly  made  up  of  lymphocytes  or  plasma  cells. 
In  other  words,  the  lymphoc)rte  is  the  cell  upon  which  the  host  relies  for  protection 
against  the  tubercle  bacillus.  It  is  also  the  cell  which  is  called  forth  in  .syphilitic 
lesions,  therefore  the  possibility  has  occurred  to  me,  that  syphilis  is  primarily 
responsible  for  some  of  the  cases  falling  into  this  intermediary  group. 

I  have  been  surprised  at  the  number  of  cases  which  have  given  a  positive 
Wassermann  reaction.      This   in   itself  means  nothing,  but  when  it  is  found,  as  it 


558  BIOLOGY   OF   INFLAMMATION   AND   MALIGNANT   DISEASE. 

has  been  my  experience,  that  the  cases  which  give  a  positive  Wassermann 
reaction  improve  under  salvarsan,  while  those  which  give  a  negative  do  not 
improve,  and  are  often  made  worse,  a  relationship  between  syphilis  and  the  inter- 
mediary aleucaemic  lymphoc)rtomata  does  suggest  itself. 

Eecently  I  have  had  four  patients  whose  cases  make  still  further  suggestive  the 
possibility  afore-mentioned. 

Case  87.^A  man,  aged  39  years,  contracted  syphilis  fifteen  years  ago,  for  which 
he  was  treated  with  mercury  internally  for  three  years.  Five  years  after  the 
infection,  diffuse  swellings  appeared  in  the  neck,  and  mainly  affected  the  salivary 
glands  and  the  lymphatic  glands  around.  In  spite  of  the  most  vigorous  anti- 
syphilitic  treatment,  the  glands  remained  umnoved.  During  the  ten  years  before 
I  saw  him,  the  patient  had  frequent  attacks  of  oedema  over  various  parts  of  the 
body,  and  they  not  infrequently  commenced  either  in  or  around  the  lachrymal  glands, 
which  spread  to  the  neck,  necessitating  frequent  tracheotomy,  and  finally  a 
permanent  tracheotomy  tube  had  to  be  worn.  Around  the  enlarged  glands  the 
oedema  was  chronic.  At  frequent  intervals,  patient  developed  swelUugs  in  his 
skin,  and  they  ultimately  burst,  leaving  small  holes  which  were  extremely  deep, 
not  at  all  like  gummata.  Another  complaint  was  an  ahnost  incessant  tinnitus. 
None  of  these  symptoms  was  influenced  in  the  least  by  mercurial  inunctions  or 
injections,  or  by  iodides  administered  internally.  The  Wassermann  reaction  was  one 
of  the  strongest  I  had  ever  come  across.  The  blood-count  showed  a  diminution  of 
lymphocytes,  a  slight  increase  of  the  large  mononuclears,  and  an  increase  of 
eosinophile  leucocytes,  up  to  21  per  cent.  All  the  tuberculin  tests  were  negative. 
A  piece  of  lymphatic  gland  was  removed  for  microscopic  examination,  and  revealed 
the  following  points  : — 

Capsule  thickened ;  follicles,  on  the  whole,  well  maintained;  where  other  follicles 
should  have  been,  was  a  cellular  infiltration  made  up  of  alternating  lymphocytes 
and  plasma  cells,  but  characterised  by  some  endothelial  cells  with  young  IjTiipho- 
cytes  in  their  protoplasm,  and  also  a  number  of  endothehal  cells  whose  nuclei  were 
undergoing  division  like  Sternberg's  multinucleated  giant  cells.  Throughout  the 
cellular  infiltration  were  several  eosinophile  cells. 

Such  a  histological  picture  is  certainly  not  that  of  syphilis,  but  one  of  what 
would  have  been  called  lymphogranulomatosis  or  Hodgkiu's  disease. 

When  treated  with  salvarsan,  an  ulcerated  nodule  on  the  chest  healed  at  once, 
the  glands  went  down  to  almost  their  normal  size,  the  attacks  of  oedema  became 
very  much  less  frequent,  and  the  tinnitus  was  diminished.  This  was  doubtless  a 
case  of  mixed  Hodgkiu's  and  Miculicz's  disease  of  syphilitic  origin,  with  Mycosis 
fungoides  as  cutaneous  lesions. 


ROLE    PLAYED    BY   LY-JIFHOCYTE. 


559 


Case  88. — A  boy,  aged  21  years,  contracted  syphilis  November.  1913.  I  saw 
him  first  in  January,  L9H,  when  he  showed  the  remains  of  a  chancre  on  his  penis 
and  a  papular  rash,  but  he  was  covered  from  head  to  foot  with  what  appeared  to  be 
a  diffuse  pigmented  erythrodermia,  upon  which  were  innumerable  urticarial  and 
prurigo-like  lesions,  some  of  which  had  pu.s  in  them,  owing  to  a  secondar}"-  infection 
caused  by  the  intense  itching  accompanying  the  eruption. 

It  was  difficult  to  distinguish  tlie  syphilitic  papules  from  the  rest. 

The  glandular  enlargement  was  very  marked,  especially  the  two  inguinal  .sets, 
and  they  certainly  were  more  enlarged  than  one  would  expect  to  see  in  an  early 
.syphilitic  infection. 

Thinking  the  sji-philis  might  have  given  rise  to  an  intermediary  form  of  the 
aleucaemic  lymphocytomata  of  the  lyniphatic  glands,  with  a  secondary  prurigo- 
like  eruption,  I  did  a  blood-count  with  the  following  striking  re.sult : — 

White  blood  corpu.scles 

Red         „  „  ... 

Haemoglobin 

Colour  index 


Differential  count  of  whites 

Polymorphonuclears 
Ljmiphocj^-es 
Large  mononuclears 
Eosinophiles 
Basophiles 


26,000 

per  c.nau. 

. .   4,960,000 

)) 

. .   90 

per  cent. 

0 

9    „ 

Per  cent. 

Per  c.mm 

. .  65 

16,900 

..12 

3,120 

2'2 

572 

..  20-0 

5,200 

..   0-8 

208 

This  shows  a  polymorphonuclear  leucoc3rtosis  with  a  marked  eosinophilia, 
not  a  blood-count  one  would  expect  to  get  in  the  early  generalisation  stage  of  syphilis. 

After  seven  weekly  injections  of  neo-salvarsan  and  a  few  intramuscular  injec- 
tions of  grey  oil,  the  blood-count  was  done  again.  In  the  meantime  the  syphilitic 
symptoms  had  vanished,  the  prurigo-like  eruption  had  improved,  but  by  no  means 
gone,  and  some  of  the  individual  lesions  had  increased  somewhat  in  size.  The 
glandular  enlargement,  though  not  so  marked,  still  persisted  : — 


White  blood  corpuscles 
Red  „  ,, 

Haemoglobin 
Colour  index 


12,000  per  c.mm. 
5,680,000 

95  per  cent. 
0-8     „ 


560  BIOLOGY   OF   INFLAMMATION   AND    MALIGNANT    DISEASE. 

Differential  count  of  whites  : — 


Per  cent. 

Per  c.mm 

Polymorphonuclears 

60 

7,200 

Lymphocytes 

23 

2,760 

Large  mononuclears 

4 

480 

Eosiuophiles 

11-4 

1,368 

Basophiles  . . 

1-6 

192 

The  above  count  shows  a  slight  polymorphonuclear  leucocjrtosis,  with  still  a 
marked  eosinophilia. 

The  Wassermanu  reaction  was  still  markedly  positive.  Unfortunately  I 
could  not  remove  a  gland  for  microscopic  examination,  but  the  outbreak  of  the 
prurigo-like  eruption,  accompanied  by  a  great  enlargement  of  the  lymphatic  glands 
early  in  the  stage  of  generalisation  of  the  syphilitic  virus,  together  with  a  blood- 
count,  as  above,  and  the  way  in  which  the  whole  picture  altered  under  specific 
treatment,  strongly  suggests  not  only  that  the  prurigo-like  eruption  was  a  symptom 
of  an  aleucaemic  lymphocjiioma,  but  also  that  syphilis  was  the  cause  thereof. 

The  other  two  cases  were  men  with  strong  syphilitic  histories,  who  developed 
enormous  glandular  enlargements  in  the  mediastinum.  In  both,  the  Wassermann 
reaction  was  positive,  and  in  both  the  diagnosis  of  aneurysm  was  made,  although 
all  the  clinical  signs  pointed  against  such  a  diagnosis,  and  both  were  markedly 
improved  by  salvarsan. 

Summary. 

Growths  in  which  the  lymphocyte  predominates,  should  receive  the 
name  of  lymphocytomata.  They  may  primarily  afiect  the  skin,  other  viscera, 
lymphatic  glands,  spleen,  and  bone-marrow,  and  they  may  either  run  a  leucaemic 
or  an  aleucaemic  course.  The  aleucaemic  forms  may  be  either  innocent  or 
malignant,  and  intermediary  stages  occur  between  the  two. 

Skin. 

(a)  Leucaemic  hjmpliocytomata. — True  leucaemic  nodules,  or  even  diffuse 
swellings,  may  appear  in  the  skin.  The  disease  may  remain  aleucaemic  for  a  time, 
but  ultimately  it  ends  in  true  lymphatic  leucaemia. 

{b)  Aleucaemic  lymphocytomaia. — These  may  be  either  innocent  or  malignant. 
The  innocent  lymphoc)d;omata,  or  plasmomata,  as  they  are  usually  called,  since  the 
l}aiiphoc}i;es  have  mostly  developed  into  plasma  cells,  are  caused  by  various  infective 
agents,  such  as  syphilis,  tubercle,  etc. 


ROLE    PLAYKD    BY    LYMPHOCYTE.  561 

The  nialiguaut  lympliocytoiuata  are  primary  sarcomata,  arising  from  lympho- 
cytes, plasma  cells,  and  endothelial  cells.  Between  the  innocent  and  mahgnaut 
aleucaemic  lymphocytomata  of  the  skin,  various  links  in  the  lymphocytic  portion 
of  the  niesoblastic  chain  are  to  be  met  with.  Clinically,  the  conditions  are  very 
much  alike,  and  histologically  no  hard  and  fast  line  can  be  drawn  between  them. 
They  comprise  Mycosis  fungoides,  Lymphodermia  perniciosa,  which  is  probably 
the  same  condition  as  the  French  mycotic  erythrodermia,  and  Lymphogranulo- 
matosis cutis. 

The  Mycosis  fungoides  is  nearest  the  inflammatory  end  of  the  innocent  link, 
while  Lympliogranulomatosis  cutis  is  nearest  the  sarcoma  end  of  the  malignant 
link ;    between  the  two  every  kind  of  variation  is  to  be  met  with. 

The  intermediate  stages  can  be  understood  better,  if  the  histological  changes 
are  studied,  and  no  name  is  given  to  any  one  stage. 

The  lymphocyte  has  its  origin  in  endothelial  cells,  and,  when  adult,  it  gives 
rise  to  plasma  cells.  The  cause  of  the  plasmoma  may  be  of  a  more  irritating  nature 
than  that  met  with  commonly,  in  syphilitic  and  tuberculous  lesions  for  instance. 
To  protect  the  host,  the  plasma  cell  can  break  up  its  protoplasm,  cause  its  nucleus 
to  divide  and  subdivide,  cause  a  similar  change  to  take  place  in  the  nucleolus,  and 
finally  the  nucleolus  may  take  upon  itself  the  whole  responsibility  of  resisting  the 
attack,  when  it  behaves  like  a  parasitic  body,  and  simulates  those  j^seudo-parasitic 
bodies  to  be  met  with  in  malignant  epitheliomata,  and  these  I  demonstrated  as 
arising  from  the  nucleoli  of  epithelial  cells. 

The  lymphocyte  itself  may  go  through  the  same  changes,  so  far  as  its  nucleus 
and  nucleolus  are  concerned.  The  lymphocyte's  progenitor,  the  endothelial  cell, 
may  do  likewise.  Therefore,  the  difference  in  these  various  skin  lesions  is  one  of 
degree,  depending  upon  the  kind  of  attack,  the  kind  of  resistance  offered,  and  the 
cell  fii'st  attacked.  It  will  now  be  seen  that  there  is  a  true  primarily  innocent  and 
a  primarily  malignant  aleucaemic  cutajieous  Ijanphocytoma,  and  that  between 
these  two  end  links  are  several  connecting  links,  which,  instead  of  going  by  the 
names  Mycosis  fungoides,  Lymphodermia  perniciosa  and  Lymphogranulomatosis 
cutis,  should  be  called  intermediary  aleucaemic  cutaneous  lymphocjiiomata  ' 
affecting  chiefly  this  or  that  transformation  of  the  plasma  cell,  lymphocyte,  and 
endothelial  cell. 

My  own  opinion  is  that  from  any  poison,  be  it  bacillary  or  chemical,  which  is 
attacked  by  lymphocytes,  such  as  is  the  case  in  syphilis  and  tuberculosis,  provided 
the  call  for  protection  is  sufficiently  concentrated  and  prolonged,  any  l>-niphoc}'tonia 
may  result.  As  to  which  one  results,  will  depend  upon  the  situation  of  the  call,  the 
concentration  of  the  call,  etc.,  so  that  if  it  starts  in  the  skin,  it  will  be  a  form  of 

2n2 


562  BIOLOGY    OF   INFLAMMATION    AND   MALIGNANT   DISEASE. 

what  was  called  Mycosis  fungoides  ;  if  it  begins  in  the  salivary  glands,  it  will  be  a 
form  of  Miculicz's  disease  ;  and  if  it  commences  in  the  lymphatic  glands,  it  will  be 
a  form  of  what  was  called  Hodgkin's  disease.  The  concentration  or  severity  of  the 
call  will  be  gauged  by  that  stage  in  the  life  history  of  the  lymphocyte  which. pre- 
dominates. According  to  which  stage  is  aiTected,  the  degree  of  malignancy  or 
innocency  can  be  determined.  As  to  whether  the  condition  is  malignant  or  not, 
can  be  ascertained  by  judging  the  degree  of  the  nuclear  and  nucleolar  activity  of 
the  cells.  Wliat  has  just  been  stated  about  the  skin,  may  be  applied  equally  well 
to  the  lymphatic  glands  and  the  spleen,  hence  an  enumeration  of  the  various 
lymphocytomata  affecting  these  organs,  requires  no  furtlier  elaboration. 

>  Untia  (1913),  "  Biochemie  dcr  Haut,"  Gustav  Fischer,  Jena. 
-  McDonagh  (1914),  "  Aichiv.  fur  Derm.  u.  Syph.,"  cxx,  289. 
3  McDonagh  and  Mackenzie  Wallis  (1913),  "  Biochemical  .Journ.,"  vii,  517. 
••  McDonagh  (1914). — "  A  report  upon  the  Biology  of  Syphilis,"  Harrison  &  Sons,  London. 
5  Pighini  (1912),  "  Biochem.  Zcit.."  xlii,  124 

"  Paltauf  u.  V.  Zumbusch  (1914),  "  Archiv  fiir  Derm.  u.  Syph.,"  cxviii,  699. 
'  Sternberg  (1898),  "  Ztschr.  f.  Heilk.,"  cxix,  21. 
«  Anidt  (1912),  "  Virehow's  Archiv.,"  ocix,  432. 

'■>  Zeigler  (1911),  "  Die  Hodgldnsche  Krankheit,"  Gustav  Fischer,  Jena. 
"^  Naegoli  (1913),  "  Leukamie  u.  Pseudoleukamie,"  Alfred  Holder,  Wien  u.  Leipzig. 
"  McDonagh  (1911),  '"  Archiv.  fur  Derm.  u.  Syph.,"  cix,  441. 
'2  Hazen  (1913),  "Journ.  Cut.  Dis.,"  xxxi,  618,  759. 
"  Unna  (1910),  "  Histolog.  Atlas  zur  Path,  der  Haut,"  L.  Voss,  Leipzig. 
''  Sibley  (1914),  "  Brit.  Journ.  of  Dermat.,"  xxvi,  3(51. 
'*  Ziegler  (1906),  "  Histogenese  der  Myeloiden  Leukamie,"  G.  Fischer,   Jena. 


CHAPTER   XLVII. 

THE  ROLE   PLAYED  BY  AN  ENDOTHELIAL  CELL  IN  INFLAMMATION, 
AND   ITS  PROBABLE   RELATIONSHIP  TO  SARCOMA. 

Ill  the  last  chapter,  the  endothelial  cell  was  considered  secondarily,  or  only 
in  so  far  as  it  affected  the  lymphocyte.  The  sum  of  the  evidence  brought  forward 
relating  to  the  endothelial  cell  was,  that  if  the  call  for  protection  affected  the 
lymphocyte-producing  endothelial  cells  first  and  foremost,  the  endothelial  cells 
behaved  like  sarcoma  cells,  so  that  the  lesion  or  lesions  produced  were  actually 
malignant. 

The  lymphocyte-producing  endothelial  cells  are  probably  the  endothelial  cells 
of  the  lymphatic  system  only,  and  those  which  we  are  about  to  discuss  are  probably 
the  endothelial  cells  of  the  vascular  system  mainly. 

The  vascular  endothelial  cells  can  be  aft'ected  in  inflammation  and  in  new  growth, 
and  a  chain  can  be  formed  connecting  these  two  terminal  links,  similar  to  the 
epithelial  and  lymphocytic  chains  already  described. 

Inflamm.\tory  Endothelioma. 

Chemical  poisons  appear  to  be  the  chief  cause  of  inflammatory  cndotheliomata, 
the  following  case  being  a  verA'  good  example  of  this  group  : — 

Case  89. — A  woman,  over  3.5  years  of  age,  whenever  she  took  iodides  internally — 
as  she  was  accustomed  to  do,  by  taking  Clarke's  blood  mixture  periodically — used  to 
develop  peculiar  papular  skin  lesions  around  the  elbows  and  knees.  When  the 
rash  came  out,  she  would  lose  her  voice  and  get  threatened  attacks  of  oedema 
of  the  glottis.  The  papular  lesions  varied  in  size  according  to  the  stage  of  their 
development,  the  biggest  being  not  larger  than  a  pea.  The  early  lesions  had  a 
central  haemorrhagic  spot,  which  in  the  older  papules  had  given  way  to  a  yellow 
spot,  considerably  bigger  than  the  original  haemorrhagic  spot.  In  some  of  the 
oldest  papules,  a  crust  occupied  the  centre. 

The  skin  lesions  disappeared  in  course  of  time  when  the  iodides  were  stopped. 
On  examination,  nothing  abnormal  was  found,  and  the  urine  was  natural. 


564  BIOLOGY    OF   INFLAMMATION   AND    MALIGNANT   DISEASE. 

A  histological  examination  of  a  very  early  lesion  revealed  the  following  points. 
The  epithelium  was  thinned  over  the  centre  of  the  papule,  and  directly  under  it 
was  a  dilated  capillary  almost  filled  with  endothelial  cells.  Many  of  the  endothelial 
cells  had  reached  the  tissue  outside.  In  the  endothelial  infiltration  were  numerous 
red  blood  corpuscles  and  leucocytes.  In  the  corium  on  either  side  of  this  central 
cellular  mass,  all  the  capillaries  were  dilated  and  filled  with  numerous  endothelial 
cells,  many  of  which  had  extended  outside  the  walls,  where  there  were  no  red  or 
white  blood  corpuscles. 

In  the  later  lesions,  the  peripheral  endothelial  proliferation  was  more  pro- 
nounced, but  in  the  central  mass  the  endothelial  cells  had  degenerated  and  practically 
the  whole  space  was  taken  up  with  leucocytes.  Many  of  these  leucocytes  were  pus 
cells  ;  hence  the  disappearance  of  the  epithelium  above  them,  and  the  explanation 
of  the  crust. 

Except  for  a  fatty  degeneration  which  some  of  the  endothelial  cells  in  the 
central  mass  had  undergone,  those  in  the  peripher}^  had  not  altered.  The  j^ellow 
colour  and  xanthomatous  appearance  of  the  late  lesions  was  probably  partly  due 
to  this  fatty  degeneration. 

The  endothelial  cells  were  somewhat  swollen,  but  both  the  protoplasm  and  the 
nuclei  stained  well.  The  protoplasm  was  sharply  circumscribed,  the  cells  were 
always  mononuclear,  and  each  nucleus  had  its  single  nucleolus.  Histologically, 
the  lesion  was  a  true  inflammatory  endothelioma,  and  the  leucocj^ic  infiltration, 
which  never  extended  beyond  the  centre  of  the  lesion,  was  purely  secondary. 

Xanthoma  and  xanthelasma  are,  in  my  opinion,  inflammatory  endotheliomata, 
caused  by  variou.s  chemical  poisons  which  are  not  uncommonly  generated  in 
metabolic  diseases,  such  as  diabetes,  etc. 

Xanthoma  has  always  received  a  great  deal  of  attention,  because  of  the  striking 
appearance  of  the  lesions.  The  yellow  colour  is  due  to  a  peculiar  degeneration 
which  the  protoplasm  of  the  endothelial  cells  undergoes.  It  is  of  the  nature  of  a 
fatty  degeneration,  but  the  chemical  products  formed  are  not  the  same  in  all 
instances.  Sometimes  the  xanthoma  masses  stain  with  both  osmic  acid  and 
Sudan  III.  In  other  cases  they  stain  only  with  Sudan  III.  The  masses  may  be 
very  optically  active,  and  may  be  found  to  consist  of  cholesterol,  but  this  is  not 
true  of  all  cases. 

Pigment,  in  the  epithelial  cells,  is  a  degeneration  product  of  the  protein  of  the 
cell,  and  its  formation  is,  at  the  same  time,  a  functional  action.  In  some 
inflammatory  conditions,  the  pigment  is  very  markedly  increased,  so  that  one  can 
draw  a  parallel  between  the  pigment  degeneration  of  the  epithelial  cells  and  the 
xanthomatous  degeneration  of  the  endothelial  cells. 


ROLE    PLAYED    BY   ENDOTHELIAL   CELL.  565 

The  so-called  senile  angiomata,  are,  most  probably,  inflammatory  endo- 
theliomata. 

New  Growth  Endotheliomata. 

Instead  of  behaving  as  they  do  in  inflammation,  a  group  of  endothelial  cells 
may  multiply  and  form  a  new  growth,  and  this  new  growth  may  be  either  innocent 
or  malignant.  There  is  a  type  of  cutaneous  endothelioma,  thoiigh  rare,  which 
corresponds  to  the  basal-celled  epithelioma  (rodent  ulcer).     I  have  had  two  cases. 

Cases  90,  91. — Both  cases  were  men  nearly  50  years  of  age.  In  the  one,  a  growth 
appeared  on  the  ala  of  one  nostril,  and  gradually  grew  to  the  size  of  a  pea ;  the 
tumour  then  ulcerated  and  looked  very  much  Uke  a  rodent  ulcer — indeed,  it  was 
diagnosed  as  such.  The  growth  was  removed  and  microscopically  examined,  when 
it  turned  out  to  be  a  true  endothelioma.  The  growth  recurred.  In  the  other  case, 
two  growths  appeared  on  the  back  ;  they  were  about  the  same  size  as  that  just 
described,  but  they  did  not  ulcerate.  When  removed  they  did  not  recur,  and 
histologically,  the  characters  of  all  three  growths  were  the  same. 

The  endotheliomata  about  to  be  described  correspond  to  the  papillomata,  and 
like  them,  they  may  be  either  innocent  or  malignant. 


Moles. 

A  mole  is  frequently  called  a  naevus,  and  as  there  appears  to  be  so  much 
confusion  about  these  two  words,  no  harm  will  be  done  by  analysing  the  true 
meanings  of  the  two  words. 

The  word  mole  comes  from  the  Anglo-Saxon  word  "mfil,"  which  means  a  spot,, 
and  the  Latin  word  "  naevus"  means  a  blemish.  Hence  the  two  words  have  the 
same  meaning.  The  word  mole  is  most  frequently  given  to  the  pigmented  or  non- 
pigmented  congenital  growths  of  the  skin,  while  the  word  naevus  is  usually  meant 
to  designate  some  congenital  vascular  growth,  although  very  often  the  two  words 
are  used  indiscriminately  for  the  same  lesion.  As  so  much  confusion  surrounds 
these  two  words,  it  would  be  very  convenient  if  we  used  them  loosely  for  any 
blemish  of  the  skin,  remembering  at  the  same  time  that  both  words  meant  the 
same  thing.  If  we  wanted  to  discriminate  between  the  various  kinds  of  lesions 
which  fall  under  these  two  names,  pathological  aid  should  be  invoked,  and  the 
growth  named  according  to  the  cells  of  which  it  was  constituted.  Moles  and  naevi 
are  epitheliomata  and  endotheliomata.  The  latter  may  be  roughly  divided  into 
pigmented  and  non-pigmented  endotheliomata,  haemangioendotheliomata,  and 
lymphangioendotheliomata. 


566  BIOLOGY   OF   INFLAMMATION   AND    MALIGNANT   DISEASE. 

Pigmented  and  Non-pigmented  Endotheliomata. 
Discussion  lias  raged  for  years  about  the  origin  of  mole  cells,  and  the  question 
is  by  no  means  settled  yet.  Doubtless  some  of  the  confusion  is  due  to  the  fact 
that  the  words,  moles  and  naevi,  have  not  the  same  significance  for  any  two  observers. 
Moles  and  naevi  can  be  either  epitheliomata  or  endotheliomata,  the  latter  being 
more  frequently  met  with  than  the  former.  The  epitheliomata  have  already  been 
discussed,  so  in  this  chapter  the  endotheliomata  will  be  considered. 

What  most  people  commonly  regard  as  moles,  are,  in  my  opinion,  endothe- 
liomata. Some  of  the  pigmented  endotheliomata  are  difficult  to  distinguish 
clinically  from  the  pigmented  epitheliomata.  Microscopically,  they  can  be  more 
easily  differentiated.  As  the  name  mole  is  given  to  the  clinical  condition,  whether 
the  lesion  is  microscopically  an  epithehoma  or  an  endothelioma,  it  has  resulted  in 
the  formation  of  two  camps. -^  2  3  6  7  8  9  lo  q,^  ^jjg  q^^  ^-^^^  j|-  jg  thought  that 
all  moles  are  epitheliomatous,  while  on  the  other  side  the  opinion  is  held  that  they 
are  all  endotheliomatous.  At  one  time,  all  histologists  considered  moles  to  be 
endotheliomata,  but  now  most  are  leaning  towards  the  other  view. 

As  already  stated,  I  think  moles  may  be  either  epithehomata  or  endothehomata, 
but  that  the  latter  are  more  commonly  to  be  met  with  than  the  former.  Hence 
I  propose  to  advance  points  against  those  who  maintain  a  common  epithelial  origin, 
as  their  case  is  certainly  the  weaker. 

The  two  reasons  which  are  given  by  those  who  maintain  the  epithelial  origin 
view  are  :  (1)  that  they  have  witnessed  the  gradual  transition  of  epithelial  cells 
into  mole  cells  ;    (2)  because  the  mole  cells  sometimes  contain  pigment. 

In  ordinary  inflammatory  skin  lesions,  it  is  not  at  all  uncommon  to  see  several 
stray  epithelial  cells  in  the  inflammatory  infiltration.  The  inflammatory  infiltration 
very  often  reaches  right  up  to,  and  presses  on  the  epidermis,  but  as  the  wandering 
epithelial  cells  are  so  distinct  from  the  inflammatory  cells,  a  transition  between 
the  two  is  inconceivable.  If,  on  the  other  hand,  mole  cells  are  in  place  of  the 
inflammatory  cells,  one  might  easily  run  away  with  the  idea  that  in  those  cases  in 
which  the  mole  cells  had  encroached  to  the  epidermis  and  the  basal  layer  had 
been  broken,  owing  to  the  obliquity  of  the  cut  section,  several  epithelial  cells 
might  be  seen  amongst  the  mole  cells,  and,  owing  to  the  similarity  of  the  two, 
that  a  gradual  transition  had  taken  place.  Naturally,  in  the  epitheliomatous  moles 
a  transition  can  be  seen,  but  it  does  not  follow  that  such  a  transition  is  to  be 
seen,  somewhere,  in  all  moles. 

That  the  cells  are  sometimes  pigmented,  is  no  evidence,  since  pigmentation  is, 
after  all,  only  a  degeneration  product  of  protein,  and  is  by  no  means  peculiar  to 
epithelial  cells.     Plates  43  and  44  are  from  a  pigmented  epitheliomatous  mole. 


ROLE    PLAYED    BY    ENDOTHELIAL   CELL.  567 

In  favour  of  mole  cells  usually  being  endothelial  cells  are  the  following  facts  : — 

They  most  commonly  occur  in  the  centre  between  two  papillary  processes, 
and  it  is  in  the  centre  that  the  capillaries  are  most  abundant.  The  papillary 
processes  are  often  greatly  lengthened,  but  still  a  wide  space  often  exists  between 
the  mole  cells  and  the  epidermis  above,  and  the  papillae  laterally.  The  basal 
layer  of  the  epidermis  is  often  markedly  pigmented  when  the  mole  cells  contain 
no  pigment. 

Mole  cells  may  become  malignant,  and  then  they  behave  as  sarcomata.  Let  us 
consider  a  rodent  ulcer  for  a  moment.  A  rodent  ulcer  is  a  basal-celled  epithelioma 
and.  in  every  case,  a  connection  can  be  traced  between  the  growth  and  the 
epidermis.  This  is  likewise  the  case  with  all  new  growth  epitheliomata.  Those 
which  have  no  connection  with  the  epidermis  itself  are  appendicular  epitheliomata, 
and  the  cells  of  the  growth  correspond  to  the  layer  of  the  appendicular  structure 
from  which  it  arises.  If  it  forms  from  mature  tissue,  the  cells  constituting  the 
growth  will  resemble  those  of  hair  follicles,  or  sweat  or  sebaceous  glands.  If  it  forms 
from  embryonic  tissue,  the  growth  will  be  like  a  rodent  ulcer,  made  up  of  basal 
epidermal  cells,  the  basal  epidermal  cell  being  the  embryonic  epidermal  cell,  from 
which  all  the  other  cells  ultimately  mature. 

The  mole  cells  are  always  the  same  ;  they  are  mature  endothelial  cells.  If 
they  arise  from  epithelial  cells,  they  must  arise  from  mature  epithelial  cells  and 
alwavs  from  the  same  layer,  as  the  mole  cells  do  not  vary. 

The  epithelial  cell  layer,  to  which  the  mole  cell  most  approximates,  is  the  third 
or  fourth,  and  this  is  usually  not  pigmented. 

If  the  mole  cells  arise  from  such  a  mature  epithelial  cell,  how  can  it  be 
explained  that  they  never  arise  from  the  mature  appendicular  cells,  but  onl}'  from 
the  epidermis  proper  ?  and  why,  in  over  90  per  cent,  of  the  specimens,  does  a  space 
separate  the  epithelial  cells  from  the  mole  cells — a  phenomenon  which  is  never 
witnessed  in  new  growth  epitheliomata  arising  from  the  epidermis  proper  ? 

Furthermore,  keratinisation  is  a  common  feature  of  epitheliomata,  while  mole 
cells  are  unknown  to  develop  keratin. 

When  an  epithelial  cell  forms  pigment,  the  nucleus  is  somewhat  swollen,  and 
there  is  a  marked  activity  of  the  nucleoli.  The  pigment  is  granular,  and,  in  most 
cases,  limited  to  the  cell. 

When  a  mole  cell  is  pigmented,  there  appears  to  be  no  increased  activity  of 
tlie  nucleus  or  of  the  nucleolus,  i.e.,  provided  it  is  not  malignant.  Note  that  the 
nucleoh  in  the  mole  cells  are  not  so  well  marked  as  they  are  in  epithelial  cells.  The 
pigment  is  more  massted,  not  so  distinctly  granular,  and  is  far  from  being  limited 
to  the   cell    in  which    it    is    formed,  it    is   often    fainter    in   colour,  and  although 


568  BIOLOGY   OF   INFLAMMATION   AND    MALIGNANT   DISEASE. 

true  melanin,  it  behaves  differently  to  reagents  from  the  normal  epithelial 
melanin. 

Moles,  or  naevi,  which  may  be  either  pigmented  or  unpigmented,  are,  in  my 
opinion,  usually  new  growth  endotheliomata.  The  epitheliomatous  mole  can 
readily  be  distinguished  microscopically  from  the  endotheliomatous  mole,  and 
very  often  the  two  can  be  differentiated  clinically,  since  ulceration  is  a  common 
feature  of  the  former,  and  not  of  the  latter. 

The  so-called  melanotic  sarcomata,  or  melanomata,  are,  in  my  opinion,  new 
growth  endothelial  cells,  the  nuclei  and  nucleoli  of  which  behave  in  the  same  way 
as  those  of  the  cancer  and  sarcoma  cells  already  described. 

These  malignant  endotheliomata  need  not  necessarily  be  pigmented.  They 
may  start  de  novo  as  sarcomata,  or  the  ordinary  mole  cells,  i.e.,  the  ordinary 
new-gro^vth  endotheliomata,  rnay  become  malignant. 

The  endotheliomata  to  be  now  described,  correspond  to  the  appendicular 
epitheliomata  and  the  mixed  epithelial  and  appendicular  epitheliomata,  and,  hke 
them,  are  practically  never  malignant,  because  the  cells  in  all  are  onl}'  semi- 
embryonic. 

Haemangioendotheliomata. 

Although  haemangioendotheliomata  are  congenital  growths,  the  patient  need 
not  necessarily  be  born  with  them.  Usually  they  appear  within  a  few  years  of 
birth,  but  occasionally  they  may  not  become  manifest  until  the  patient  has  reached 
middle  life.  The  lesions  are  multiple,  they  occur  anywhere  on  the  skin,  they  vary 
from  the  size  of  a  pin's  head  to  that  of  a  sixpenny  piece,  they  are  raised  above  the 
surface  of  the  skin,  and  have  a  red  or  brownish-red  colour.  The  lesions  may 
spontaneously  disappear,  or  they  may  undergo  changes  before  they  vanish,  in  which 
case  the  colour  of  the  lesions  varies  enormously,  some  may  be  brown,  others  yellow-, 
and  others  quite  white.  Having  had  some  cases  under  my  care,  the  pathology  of 
which  I  have  had  ample  opportunities  for  studying,  it  would  be  as  well  to  copy  the 
paper  which  appeared  in  the  "  British  Journal  of  Dermatology,"  under  the  name 
of  Naevo-Xantho-Endothehomata.* : — 

Case  92. — In  June,  1906,  a  child  was  brought  up  by  its  mother  to  St. 
Bartholomew's  Hospital,  under  the  care  of  Dr.  Morley  Fletcher,  to  whom  I  am 
indebted  for  the  case,  for  some  "  yellow  swellings  "  which  it  had  scattered  about 
the  bod3^ 

The  face  was  the  part  most  affected,  especially  the  eyelids.  There  were  two 
swellings  in  the  neck,  one  on  the  left  arm,  one  or  two  on  both  legs,  and  a  few 
scattered  about  the  trunk.     To  look  at,  they  were  bright  yellow,  slightly  depressed 


♦    -    ,«.  \    *  V        .    •    ♦  ^\     •^iSf 


■•>0::rv?:-v:'>-7»:i 


Facing  p.  568. 


ROLE   PLAYED   BY   ENDOTHELIAL   CELL.  569 

in  the  centre,  and  had  a  glazed  surface  resembling  very  closely  Xanthoma  j^lanum. 
The  edge  of  each  swelling  was  reddish,  and  the  vessels  could  plainly  be  seen. 

The  tumours  in  size  varied  from  \  in.  to  J  in.  in  diameter.  They  were  raised 
about  3  or  4  mm.  above  the  surface,  were  of  firm  consistency,  and  moved  with  the 
surrounding  skin,  which  was  in  every  way  normal.  In  other  respects  the  child  was 
quite  healthy. 

AVhat  urine  could  be  obtained  was  carefully  examined,  but  nothing  abnormal 
was  discovered — no  sugar,  bile  or  albumin.  These  swellings  were  present  at  birth, 
and  the  following  account  is  taken  from  the  notes  of  Mr.  Woodman,  who  attended 
the  confinement : — 

Born  April  7th,  1906.  L.O.A.  position.  Weight  lOj-  lbs.  About  the  body 
were  scattered  brownish-red  swellings,  raised  well  above  the  surface  of  the  skin, 
of  firm  consistency,  elastic,  almost  cartilaginous.  The  surface  of  the  tumours  was 
quite  smooth,  and  showed  numerous  small  injected  capillaries. 

In  June,  1906,  some  of  the  nodules  were  removed  for  microscopic  examination, 
and  a  painting  was  made.  I  did  not  see  the  child  again  for  a  year.  When  in  April, 
1907,  I  wi'ote  and  asked  the  mother  to  bring  the  child  up  to  hospital,  I  found  that 
the  swellings  were  of  the  same  size,  not  such  a  bright  yellow  in  colour,  and  quite 
flush  with  the  surface  of  the  surrounding  skin.  The  lesions  still  had  the  glazed 
appearance,  the  central  depression  had  disappeared,  the  edges  were  of  the  same 
colour  as  the  re.st  of  the  swelling,  and  showed  no  dilated  capillaries.  Urine  quite 
normal. 

Some  more  nodules  were  removed  for  microscopic  examination. 

Owing  to  my  being  abroad,  I  was  unable  to  see  the  child  again  till  June,  1909, 
when  I  was  surprised  to  find  all  the  swellings  had  disappeared.  The  old  scars 
resulting  from  the  biopsies  were  scarcely  visible,  and  there  was  no  keloid  formation 
in  them.  The  scar  over  the  right  eyebrow  had,  according  to  the  mother,  given  the 
child  a  good  deal  of  pain,  which  had  for  a  few  months  past  quite  disappeared.  I 
searched  the  legs,  where  I  knew  there  had  been  some  swellings,  and  all  I  could  find 
in  their  place  was  a  piece  of  skin  which  was  whiter  and  of  a  more  glazed  porcelain- 
like appearance  than  elsewhere;  so  slight  was  the  difference  that,  had  I  not  known 
that  something  had  been  there,  I  should  have  overlooked  any  change.  The  mother 
has  had  fourteen  children  ;  this  child  was  the  thirteenth,  but  none  of  the  others 
had  a  similar  condition  and  no  member  of  the  family  had  ever  suffered  from  any 
"  swellings  of  the  skin." 

Examination  oj  nodule  removed  June,  1906,  Plate  53  (1). — The  swelling  is  made  up 
of  a  cellular  infiltrationj  which  extends  from  the  epidermis  down  into  the  subcutis,  and 
measures  5  mm .  in  diameter.    It  has  a  capsule,  at  the  base  but  not  laterally,  consisting 


570  BIOLOCJY   OF   INFLAMMATION   AND   MALIGNANT   DISEASE. 

of  collagenous  and  elastic  tissue.  At  the  sides,  the  tumour  runs  into  the  normal 
connective  tissue  of  the  corium.  Above,  the  cells  of  the  growth  encroach  so  closely 
on  to  the  epidermis  that  it  is  difficult  to  say  where  one  begins  and  the  other  ends. 

Lower  down  there  is  a  sharp  division  of  the  cutis  from  the  subcutis  by  bands 
of  normal  connective  tissue  which  send  numerous  processes  into  the  cellular  mass 
above,  but  none  below,  so  that  that  part  of  the  growth  situated  in  the  subcutis 
appears  more  cellular.  Here  and  there,  the  boundary  line  is  broken,  so  that  the 
cells  of  the  cutis  are  continuous  with  those  of  the  subcutis.  The  cells  in  the 
subcutis  are  loosely  packed  together,  except  at  the  base  ;  they  lie  in  a  groundwork 
of  connective  tissue,  and  here  and  there  processes  from  the  capsule,  often 
containing  normal  blood  vessels,  are  to  be  traced  up  into  the  growth. 

The  epidermis  and  cutis  on  either  side  of  the  swelling  are  quite  normal,  and 
in  the  latter  there  is  no  sign  of  inflammation,  such  as  a  small  round-celled 
infiltration,  etc. 

Over  the  centre  of  the  tumour,  the  epidermis  is  markedly  thinned,  has  almost 
completely  lost  its  papillary  arrangement,  and  contains  no  pigment  in  the  basal 
cell  layer. 

There  is  a  parakeratosis. 

The  cellular  mass,  reaching  as  it  does  right  up  as  far  as  the  epidermis,  and 
the  similarity  of  the  cells  to  epidermal  cells,  at  first  sight  gives  the  impression  that 
the  tumour  is  epithelial  in  origin.  On  careful  examination,  the  basal  cell  layer 
has  not  given  way  in  any  part,  and  no  migration  of  an  epidermal  cell  into  the  gi'owth 
can  be  found. 

The  cells  in  the  cutis  are  mainly  polygonal  in  form,  others  are  spindle-shaped 
or  round  ;  each  contains  a  well-stained  nucleus  which  is  either  centrally  or 
excentrically  situated. 

There  is  a  good  deal  of  connective  ti.s.sue,  which  consists  of  both  collagenous 
and  elastic  tissue,  between  the  groups  of  cells,  and,  on  examining  with  a  high  power, 
the  cellular  mass  can  be  distinctly  seen  to  be  in  a  connective  tissue  groundwork. 

The  cells  of  the  subcutis  tend  to  be  more  spindle-shaped, and  there  is  not  .so  much 
intervening  connective  tissue. 

Throughout  the  specimen,  the  large  blood  vessels  are  quite  normal,  and  are 
to  be  found  in  the  connective  tis.sue  processes. 

The  capillaries  and  Ipuphatics  show  an  endothelial  proliferation,  which 
sometimes  occludes  the  lumen,  and  always  extends  outwards,  invading  the  sur- 
rounding tissue,  so  that  the  endothelial  cells  cannot  be  differentiated  from  the  cells 
of  the  growth. 

Here  and  there,  these  cells  show  signs  of  degeneration,  many  cells  put  out 


KOLE    FLAYED    BY    ENDOTHELIAL   CELL.  571 

processes  and  join  together,  resembling  a  grauuloina  wliere  f-o  many  epithelioid 
cells  join  together  to  form  a  giant-cell  in  the  centre.  This  degenerative  condition  is 
most  marked  in  the  subcntis. 

The  microscopic  picture  is  strongly  suggestive  of  an  endothelioma. 
Microscopical  examination  of  nodule  removed  April,  1907  (Plate  53  (2)). — The 
width  of  the  cellular  infiltration  is  now  only  2  mm.  With  a  low  power,  the  tumour 
seems  to  consist  of  a  mass  of  loose  cellular  connective  tissue,  extending  upwards 
almost  as  far  as  the  epidermis,  but  separated  by  an  interval  of  denser  connective 
tissue  which  is  slightly  more  cellular  than  normal. 

Downwards,  the  mass  invades  the  orbicularis  palpebrarum  mu.scle. 
The  epidermis  has  regained,  to  a  great  extent,  its  papillary  arrangement  ;  in 
some  parts  the  papillae  are  increased,  a  fact  which  is  made  still  more  evident  by 
the  flattening  out  in  other  portions. 

The  rete,  as  before,  does  not  consist  of  so  many  layers;  there  is  still  absence  of 
pigment  in  the  basal  cell-layer,  and  no  parakeratosis. 

In  the  tumour  mass,  several  large  and  quite  normal  vessels  are  to  be  seen. 
Staining  with  van  Gieson  shows  a  cellular  mass  interspersed  with  fibrous  tissue, 
to  a  much  greater  extent  than  in  the  previous  specimen,  and  also  a  layer  of  fibrous 
tissue  between  the  mass  and  the  epidermis. 

Acid  orcein  shows  a  network  of  normal  elastic  tissue,  underneath  the  epidermis 
and  scattered  about  in  the  tumour.     In  places  it  is  very  well  marked. 
This  stain  also  makes  the  vessels  in  the  section  prominent. 
In  the  healthy  tissue  around  the  tumour,  there  are  no  signs  of  inflammation. 
The  endothelial  cells  have  now  undergone  degeneration,  each  cell  is  very  much 
swollen,  and  many  have  joined  together  to  form  a  protoplasmic  mass  ;  the  proto- 
plasm appears  granular,  probably  granuloplasm,  which  give  the  cells  a  honeycombed 
appearance  ;    between   individual   cells,  or  groups   of  colls,    there  is  a  strand  of 
formed  connective   tissue,   which  comes  from  the    normal  surrounding  connective 
tissue  (Plate  53  (3)). 

Many  cells  contain  two  or  three  nuclei.  The  nuclei  are  large,  irregular  in 
outline,  and  stain  badly;  all  stages  can  be  seen,  from  commencing  degeneration  to 
complete  disappearance  of  the  cells. 

Some  of  the  blood  vessels,  those  surrounded  closely  by  the  tumour  cells,  have 
their  one  or  two  layers  of  endothelial  cells. enormously  swollen,  usually  completely 
occluding  the  lumen,  and  their  nuclei  .stain  faintly.  The  connective  tissue  of  the 
walls  is  likewise  swollen,  and  contains  no  nuclei. 

Other  blood  vessels  are  to  be  seen,  apparently  of  new  formation,  since  they 
show  no  endothelial  proliferation,  and  the  nuclei  stain  well. 


572  BIOLOGY   OF   INFLAMMATION   AND    MALIGNANT   DISEASE. 

Around  most  of  these  vessels  is  a  number  of  mononuclear  leucocytes,  easily 
distinguished  from  the  nuclei  of  the  degenerating  endothelial  cells,  by  being 
perfectly  regular  in  outline  and  by  staining  deeply.  Owing  to  the  clinical  similarity 
with  xanthoma,  sections  were  treated  with  1  per  cent,  osmic  acid  and  Flemming, 
but,  when  examined  histologically,  no  deposits  of  fat,  as  in  a  xanthoma,  were 
noticed,  but  some  of  the  cells,  markedly  those  situated  nearest  the  epidermis, 
contained  fatty  granules.  Unfortunately  none  of  the  sections  were  stained  with 
Sudan  III. 

Except  that  no  fatty  droplets  are  found,  the  cells  simulate  xanthoma 
cells  in  every  respect.  There  are  very  few  hair  follicles,  but  those  present  show 
no  pathological  change.  The  ducts  of  the  sweat  glands  cannot  be  followed  up  to 
the  epidermis,  but  the  coils  do  not  depart  in  any  way  from  the  normal.  The 
xanthoma-like  cells  surround,  but  are  never  found  intunately  connected  with 
the  cells  of  the  glands.  The  sebaceous  glands  are  few  and  far  between,  but  quite 
normal.  There  is  a  strong  similarity  between  the  cells  of  the  sebaceous  glands 
and  the  cells  under  discussion,  but  nowhere  is  any  connection  to  be  found.  Owing 
to  this  resemblance,  it  was  originally  supposed  that  xanthoma  cells  were  derived 
from  those  of  the  sebaceous  glands,  a  fact  entirely  disproved  by  the  occurrence  of 
xanthoma  masses  in  the  mucous  membranes  and  internal  organs. 

In  searching  the  literature,  I  found  a  case  described  by  Sachs^  under  the  name 
of  a  Xantlwmartiger  naevus  verrucosus,  the  histological  appearances  of  which 
coincide  with  the  specimen  just  described.  The  affection  appeared  in  the  axilla 
of  a  girl  a  few  days  after  birth. 

The  cells  depicted  resembled  abnost  exactly  the  large  cells  described  in  my 
second  specimen,  but  differed  in  that  they  contained  fat-droplets. 

The  cells  extended  up  close  to  the  epidermis,  but  did  not  go  down  as  far  as 
the  subcutis. 

They  contained  one  or  two  nuclei  which  were  either  central  or  excentric. 
Many  of  the  nuclei  showed  nucleoli,  and  in  many  cases  the  nucleus  was  shrunken. 

The  cells  resembled  very  closely  those  met  with  in  xanthoma.  By  ordinary 
hardening  and  staining,  vacuoles  took  the  place  of  the  fat-droplets,  thereby  giving 
the  cells  a  honeycombed  appearance. 

The  blood  vessels  were  somewhat  dilated,  walls  thickened,  and  the  endothelial 
cells  were  swollen,  and  projected  into  the  lumen  of  the  vessel.  The  lymphatics  were 
likewise  affected.  These  xanthoma-like  cells  occurring  in  a  naevus  led  Sachs  to 
consider  as  to  whether  he  was  dealing  with  a  pure  Xanthoma  tuberosum,  or  with  a 
soft  non-pigmented  Naevus  verrucosus.  These  xanthoma-like  cells  differed  from 
ordinary  xanthoma   cells,  in  that  they  were  arranged    in  the   papillae,   in  close 


WVi'3^MMMM 


^%^^?^ '-■:>•<  v<^^; '^■'^'•^  •  ■  ^■'S^'-^^i^^^^ 
*~^^'*  f -^  S^'J'  ''%  ■    -••-•■' 


I'\iring  p.  572, 


ROLE    PLAYED    BY    EXDOTlIELrAL   CELL.  573 

connection  with  the  epidermis,  while  the  cells  of  Xanthoma  tuberosum  are  mainly 
found  in  the  deeper  layers  of  the  cutis. 

Sachs'  case  was  one  of  a  naevus,  which  had  undergone,  presumably,  some  fatty 
degeneration  resembling  xanthoma.  The  cells  in  my  case  had  undoubtedly  under- 
gone further  degeneration,  which  is  not  unlikely,  since  spontaneous  cure  was  the 
ultimate  result,  while  Sachs'  case  remained  stationary,  and  it  is  quite  likely  that 
had  I  been  able  to  make  a  biopsy  between  the  two  periods,  the  cells  would  have 
contained  fatty  droplets,  and  would  have  resembled  Sachs'  in  every  respect.  From 
the  foregoing,  I  should  regard  the  case  as  being  a  naeviis  of  endotheUal  origin, 
which,  while  on  its  way  to  spontaneous  cure,  underwent  changes  of  a  fatty  nature, 
giving  the  lesions  the  clinical  aspect  of  xanthoma. 

Case  93. — D.  H — ,  a  girl,  aged  5  months,  was  brought  up  to  the  hospital 
by  her  mother  for  some  swelHngs  in  the  skin,  which  made  tlieir  first  appear- 
ance fourteen  days  after  birth.  There  was  absolutely  nothing  on  the  skin 
when  the  child  was  born  ;  the  swelUngs,  scattered  over  the  body,  having  no 
predilection  for  a  site,  were  about  the  size  of  a  lentil  when  they  appeared,  and  red 
in  colour.  Many  of  these  disappeared  soon  afterwards,  while  others  increased 
in  size,  became  yellow,  and  were  surrounded  by  a  reddish  halo  ;  the  yellow  swellings 
then  got  smaller  and  disappeared  spontaneously.  The  mother  states  that  she  was 
born  with  similar  swellings,  which  appeared  and  disappeared  up  to  the  age  of 
fourteen.  In  the  patient,  fresh  swellings  have  appeared  since  the  initial  outbreak. 
Although  the  tumours  resemble,  clinically,  those  met  with  in  Case  92,  they  differ  in 
that  they  were  not  present  at  birth,  and  fresh  lesions  were  formed,  but  they  are 
the  same,  inasmuch  as  spontaneous  cure  was  the  ultimate  result. 

Histology. — The  tumour  is  a  cellular  one,  which  reaches  from  the  subcutis 
(Plate  54  (1) )  up  as  far  as  the  epidermis,  being  more  cellular  in  the  subcutis.  In  the 
cutis,  the  new-formed  connective  tissue  appears  prominent  in  places,  owing  probably 
to  its  taking  the  place  of  the  cells  which  are  degenerating.  Such  an  appearance 
of  the  connective  tissue  is  only  to  be  seen  in  the  centre  of  the  tumour  ;  directly 
over  the  tumour,  the  epithelium  is  straight,  the  papillary  bodies  are  longer  and 
narrower,  their  differentiation  from  the  cellular  growth  underneath  is  difficult  to 
make  out,  the  epithelial  cells  are  degenerated,  but  under  the  high  power  no 
connection  between  the  epidermis  cells  and  the  cells  of  the  tumour  can  be 
demonstrated.  On  either  side  of  the  centre,  the  cellular  growth  does  not  reach  up 
as  far  as  the  epidermis,  and  the  epidermis  over  it  is  normal.  Examining  the 
cellular  growth  with  a  high  power,  it  is  impossible  to  differentiate  each  individual 
cell,  since  two  or  more  appear  massed  together  in  a  homogeneous  way  with  a  hyaline 
background  which  stains  faintly,  while  the  nuclei  stain  well.     Between  the  cells 


574  BIOLOGY    OF   INFLAMMATION    AND   MALIGNANT    DISEASE. 

are  numerous  spaces,  many  of  which  are  undoubted  capillaries,  since  red  blood - 
corpuscles  are  to  be  demonstrated  therein.  Many  of  these  spaces  are  lined  by  endo- 
thelial cells  which  are  continuous  with  the  cells  around,  and  the  latter  appear  to  be 
of  the  same  origin.  In  other  places  where  the  capillaries  are  distinct,  the  lumen  is 
obliterated  by  a  hyaline  mass,  around  which  are  the  well-stained  nuclei  of  the 
endothelium,  giving  the  appearance  of  a  giant-cell.  This  hyaline  mass  is  found  to 
consist  of  several  endothelial  cells.  These  endothelial  giant  cells  are  most  marked 
just  underneath  the  epidermis.  A  section  .stained  with  Sudan  III  proves  the 
presence  of  fat  in  the  cell  masses  and  in  the  protoplasm  of  the  individual  cell ;  and 
those  cells  which  fill  the  lumen  of  the  vessels,  and  which  give  the  appearance  of  a 
giant-cell,  contain  fat  in  their  .spongioplasm.  In  the  epithelial  downgro\\-ths,  there 
is  no  trace  of  fat.  Osmic  acid  preparations  bring  out  the  same  characteristics  as 
just  described  with  Sudan  III.  A  van  Gieson  preparation  shows  that  these  cells 
are  not  of  connective  tissue  origin.  A  polychrome  methylene  blue  preparation 
differentiates  well  the  epidermis  from  the  cellular  growiih,  and  as  the  connective 
tissue  is  not  stained,  the  characters  of  the  cells  are  more  easily  to  be  made  out. 
Everywhere  they  can  be  found  continuous  with  the  endothelium  of  the  blood- 
vessels, and,  in  most  cases,  they  bear  an  exact  resemblance  to  the  cells  thereof.  Some 
are  large  polygonal  cells  with  a  central  nucleus,  others  are  spindle-shaped  ;  here  and 
there,  cells  are  to  be  found  dividing  by  amitosis  ;  in  other  places,  the  protoplasm 
of  the  cell  has  disintegrated,  leaving  only  the  nucleus,  which  stains  faintly,  and 
shows  a  nucleolus. 

Case  94. — A  boy,  aged  10  months,  was  shown  by  Dr.  F.  Parkes  Weber  before 
the  Dermatological  Section  of  the  Ro^^al  Society  of  Medicine,  May,  1908,  as  multiple 
xanthoma.  The  eruption  was  confined  to  the  forehead  and  upper  part  of  the  face. 
It  consisted  of  irregularly  distributed  papules  and  raised  spots,  measuring  1-7  mm. 
in  diameter,  which  varied  in  colour  from  a  brownish-red  to  a  yellow.  The  child 
had  nothing  else  abnormal,  and  no  fre.sh  lesions  appeared  while  the  child  was  under 
observation,  and  all  of  them  spontaneously  disappeared. 

At  the  meeting,  the  case  was  regarded  as  Urticaria  pigmentosa,  a  diagnosis 
which  a  microscopic  specimen  showed  to  be  incorrect.  Unfortunately,  the 
histological  examination  was  not  worked  out,  but  there  is  no  doubt  that  the  case 
belongs  to  the  group  under  discussion. 

Case  95. — In  this  patient,  a  girl,  the  yellow  swellings  appeared  about 
three  weeks  after  birth.  According  to  the  mother's  account,  they  fii'st  appeared  as 
small  red  raised  spots,  and  became  yellow  later  ;  and  further,  that  some  of  the  yellow 
spots  remained,  while  others  disappeared  spontaneously,  leaving  no  trace  behind 
them.     In  this  case,  there  was  no  family  hi.story.     Microscopic  examination  only 


ROLE    PLAYED    BY   ENDOTHELIAL   CELL.  575 

differed  from  the  preceding  specimens,  in  that  the  cellular  gi-owth  was  not  so  large, 
that  there  were  no  giant  cells,  and  that  the  epithelial  elements  were  in  more 
abundance  and  more  pronounced. 

Case  96. — This  case  was  shown  by  Dr.  Bunch  at  the  Dermatological  Society 
of  November,  1911.  as  a  case  of  multiple  augiomata. 

The  child  was  first  seen  when  three  weeks  old,  and  the  lesions  had  been  present 
since  birth.  These  consisted  of  more  than  a  hundred  small,  purple,  raised  tumours, 
from  a  pea  to  a  small  nut  in  size,  on  the  trunk,  limbs,  face,  and  scalp.  They  became 
pale  when  pressed  with  a  diascope,  and  w«re  in  most  cases  soft  to  the  touch,  but 
one  or  two  on  the  legs  seemed  sUghtly  firmer  in  consistence. 

I  suggested  at  the  time,  that  this  case  might  belong  to  the  group  of  multiple 
benign  endotheliomata  of  the  congenital  xanthoma  type  ;  that  some  of  the  lesions 
would  ultiniatel}^  become  yellow  and  then  spontaneously  disappear. 

On  making  a  histological  examination,  the  following  was  revealed  (Plate  54  (2)): — • 

Before  coming  to  the  centre  of  the  tumour,  the  early  sections  showed  an 
increase  in  the  sweat  glands  and  ducts,  of  a  naevoid  character.  On  the  left  side 
of  the  figure,  sweat  ducts  can  be  seen  appearing  on  the  right  wall  of  the  commencing 
endothelial  growth.  As  sections  nearer  the  centre  were  examined  (Plate  54  (3)),  this 
cellular  endothelial  growth  increased  in  size,  and  in  it  were  spaces,  undoubted 
capillaries,  the  endothelial  cells  of  which  were  continuous  with,  and  of  the  same  nature 
as  those  surrounding  them.  The  cellular  growth,  then,  was  an  endothelioma.  On  the 
epidermal  side  of  the  cellular  mass  were  several  sweat  ducts,  which,  as  still  deeper 
sections  showed,  were  no  longer  visible,  owing  to  the  spreading  out  of  the  growth. 

Unfortunately,  no  fresh  specunens  were  examined,  so  it  is  impossible  to  say 
whether  any  of  the  cells  contained  fat  or  not.  There  were  no  giant  cells.  The 
jjurple  colour  of  the  lesions  was  probably  due  to  the  depth  at  which  the  cellular 
growth  was  situated,  as  the  tissues  in  between  it  and  the  epidermis  were  normal, 
and  also  to  the  fact  that  the  cells  had  not  yet  degenerated. 

Summary  of  histological  a pjjea ranees. — First  of  all,  there  is  a  dense  cellular 
growth,  most  marked  in  the  deeper  layers  of  the  skin,  the  cells  of  which  take  their 
origin  from  the  endothelium  of  the  capillaries.  Then  many  of  these  cells  disappear, 
while  new-formed  connective  tissue  takes  their  place.  It  is  in  this  stage  that  the 
giant  cells  are  to  be  seen,  some  of  which  are  formed  by  the  endothelial  cells  blocking 
a  capillary,  because  some  which  are  not  completely  blocked  contain  red  blood- 
corpuscles  ;  these  giant  cells  are  to  be  seen  under  the  epidermis.  Others — and 
these  occiir  deeper  in  the  corium — are  fomiecl  by  the  fusion  together  of  some  of 
the  cells  of  the  growth.)  The  grouping  together  of  a  dozen  or  more  cells  is  probably 
caused  by  the  growth  of  fibrous  tissue  which  separates  them.     The  cells  contain 

2o 


57G  BIOLOGY   OF   INFLAMMATION   AND   MALIGNANT   DISEASE. 

fat.  This  is  the  stage  in  which  the  lesion  microscopically  resembles  a  soft  fibroma 
or  connective  tissue  tumour.  On  careful  examination  of  the  cells  at  the  base  of  a 
tumour  removed  in  this  stage,  some  are  found  to  have  swollen  and  taken  on  the 
appearance  of  the  honeycombed  cells  to  be  now  described.  These  cells  contain 
less  fat  than  those  met  with  in  the  upper  layers  of  the  skin,  and  the  fat  appears  in 
the  form  of  granules  only. 

The  stage  further  is  when  all  the  cells  are  swollen,  contain  one  or  more  nuclei 
well  outlined  by  a  strand  of  connective  tissue,  and  have  the  honeycombed 
appearance.  It  is  now  that  the  new  vessels  appear  so  prominent,  and  signs  of 
inflammation  as  a  small  round-celled  infiltration  are  to  be  seen. 

The  final  stage  is  reached  when  these  cells  also  disappear. 

Conclusions. — From  the  foregoing  it  will  be  seen  that  there  is  a  special  form 
of  multiple  growths  in  the  skin,  and  they  are  conspicuous  from  their  yellow  colour. 

These  growths  may  be  present  at  birth,  or  they  may  not  appear  till  later,  and 
there  is  sometimes  a  family  history. 

They  may  persist  for  many  years,  but  they  tend  to  ultimate  spontaneous 
cure.  They  may  commence  as  red  tiunours,  like  angiomata,  to  become  yellow 
later. 

The  tumours  are  not  necessarily  limited  to  the  skin,  and  there  is  no_  evidence 
that  they  are  dependent  upon  any  visceral  disturbance.  They  are  new  growths, 
and  not  inflammatory  swellings. 

Concerning  the  histology,  the  views  are  various,  and  observers  have,  no  doubt, 
rather  been  led  astray  by  the  yellow  colour,  to  seek  for  them  the  same  origin  as 
Xanthoma  planum — an  inflammatory  lesion,  not  a  new  growth  ;  and  as  the 
sebaceous  gland-cells  contain  fat  and  the  cells  of  xanthoma  are  not  uiJike  them, 
these  growths  were  said  to  have  origin  from  sebaceous  glands.  Without  enumerating 
point  for  point  against  this  view,  it  sufiicies  merely  to  mention  that  these  tumours 
have  been  found  in  situations  where  there  are  no  sebaceous  glands  ;  for  instance, 
in  the  endothelium  of  the  aorta. 

The  next  common  view  held  was,  that  they  were  made  up  of  connective-tissue 
cells,  and  that  the  giant  cells  which  were  sometimes  to  be  met  with,  were  formed 
by  the  fusion  of  some  of  these  cells. 

If  the  figures  of  my  section  are  studied,  one  cannot  help  being  struck  with  the 
spaces,  the  lining  cells  of  which  are  continuous  with,  and  indistinguishable  from, 
those  surrounding  them — a  condition  one  would  not  expect  to  meet  with  in  a 
connective  tissue  tumour. 

Some  of  these  spaces,  which  I  take  to  be  capillaries  and  lymphatics,  have 
blood-cells  in  them. 


ROLE   PLAYED   BY   ENDOTHELIAL   CELL.  577 

Some  of  the  giant  cells  are  clearly  capillaries  blocked  by  swollen  endothelial 
cells,  since  in  some  which  are  not  completely  blocked,  red  blood  corpuscles  are 
visible  ;  further,  the  giant  cells  do  not  resemble  ordinary  giant  cells — a  mass  of 
protoplasm  with  nuclei  collected  at  one  pole  ;  on  the  contrary,  the  nuclei  are 
arranged  equally  all  round  the  centre,  and  the  protoplasmic  mass  can  be 
demonstrated  in  fresh  specimens  to  be  made  up  of  distinct  cells — endothelial  cells  ; 
the  nucleus  of  each  staining  only  faintly.  These  cells  contain  a  substance  which 
stains  with  Sudan  III,  and  in  the  form  of  granules,  with  osmic  acid.  The  cells 
surrounding  these  capillaries,  which  resemble  the  swollen  endothelial  cells,  also  stain 
with  Sudan  III. 

The  primary  lesion  is  probably  an  overgrowth  of  the  cells  which  should  form 
the  capillaries  and  lymphatics,  affecting  only  a  group  of  these — to  the  sweat  glands, 
for  instance,  as  in  Case  96.  Then  the  cells  undergo  some  form  of  fatty  degeneration. 
As  a  result  of  the  disappearance  of  several  of  the  cells,  the  remainder  become  more 
distinct ;  but  owing  to  the  presence  of  two  or  more  nuclei,  the  protoplasm  being 
honeycombed,  and  the  presence  of  inflammatory  cells,  these  cells  gradually  become 
more  and  more  degenerate,  until  they  themselves  completely  disappear,  normal 
blood  vessels  and  connective-tissue  cells  taking  their  place. 

The  tumours,  in  my  opinion,  are  endotheliomata,  and  belong  to  that  big  class — 
nae\nis. 

Just  the  same  as  we  can  get  an  overgrowth  of  embryonic  epithelial  tissue,  in 
the  one  case  affecting  those  cells  destined  to  form  sebaceous  gland  tissue,  in  another 
case  sweat  gland  tissue,  and  so  on,  we  can  get  an  overgrowth  of  the  embryonic 
cells  which  are  destined  to  form  the  capillaries.  The  l3aiiphatic  vessels  and 
capillaries  apparently  develop  from  cords  of  cells  that  arc  of  direct  mesodermic 
origin.  These  solid  cords  are  afterwards  hollowed  out,  and  become  tubes.  The 
lining  of  the  tubes  is  formed  from  some  of  the  cells  of  the  cords,  while  the  remainder 
form  the  coats  of  the  vessels  and  the  other  structures  which  make  up  the  connective 
tissue.  According  to  Schultze,  the  earliest  lymphatics  and  capillaries  formed  are 
those  in  the  subcutaneous  tissue.  Since  the  cells  constituting  the  tumours  are 
undoubtedly  embryonic,  one  cannot  say  for  certain  whether  the  tumours  should  be 
classed  as  endotheliomata  or  as  connective  tissue  tumours,  because  the  cells  are 
probably  in  that  stage  where  the  differentiation  is  incomplete,  and,  as  the  origin 
of  both  is  the  same,  it  matters  little.  It  is  on  account  of  the  hollowing  out  of  the 
solid  cords,  as  in  Plate  54  (.3),  and  the  later  behaviour  of  the  cells,  which  are 
undoubtedly  endothelial,  that  I  prefer  to  call  them  endotheliomata.  It  is  just 
possible,  and  Case  96  bears  this  out,  that  the  overgrowth  of  the  embryonic  cells 
which    are  destined  to   form    capillaries,  oiJy  takes  place  round  about  epithelial 

2o2 


578  BIOLOGY    OF   INFLAMMATION   AND   MALIGNANT   DISEASE. 

structures,  as  in  this  case  the  sweat  glands,  aud  that,  the  same  causes  may  be  at 
work  on  these  cells  which  produce  the  other  forms  of  naevi  from  which  scarcely  a 
person  escapes. 

In  conclusion.  I  should  suggest  that  these  tumours  under  discussion  are  naevi 
of  the  type  endothelioma,  and  that,  owing  to  a  fattj^  change  which  occurs  in  the 
cells  during  their  dissolution,  a  xanthoma-like  condition  is  produced.  The  name 
Naevo-Xantho-Endotheliomata  would  describe  them  exactly. 

Lyniphangioendotheliomata. 

Analogous  growths  in  the  skin  to  those  just  described  may  be  made  up  of 
lymphatic  and  not  vascular  endotheUal  cells.  The  only  difference  between  the  two 
lesions  is  one  of  colour,  the  lyniphangioendotheliomata  being  colourless. 

Lyniphangioendotheliomata  must  not  be  confounded  with  lymphangiomata, 
any  more  than  haemangioendotheliomata  must  be  confounded  with  haemangiomata. 
Both  haemangiomata  and  lymphangiomata  are  new  growths  of  the  vessels,  in  which 
the  endothelial  cells  do  not  participate.  Clinically,  they  are  also  very  different ; 
the  lesions  are  usually  single,  and  much  more  pronounced,  and  they  often  cover 
a  wide  area.  To  the  haemangiomata  belong  the  so-called  vascular  naevi  and  port 
wine  stains,  which  are  usually  present  on  the  child  when  it  is  born,  or  appear  soon 
afterwards.  The  lymphangiomata  are  much  more  rare,  the}'  usually  appear  later 
in  life,  the  condition  is  usually  called  Lymphangmna  circiunscriptum  cutis.  The 
whole  lesion  is  usually  about  the  size  of  the  palm  of  the  hand,  and  is  made  up  of 
a  series  of  what  look  like  distinct  vesicles.  Each  small  lesion  has  a  fluid  content, 
but  when  punctured,  it  does  not  give  rise  to  lymphorrhoea.  This  condition  must 
not  be  confounded  with  Lymphangioma  tuberosum  multiplex,  which  is  not  a 
lymphangioma  at  all,  but  a  swingoma,  i.e.,  an  epithelial  new  growth  of  the  sweat 
ducts. 

Malignant  and  Intermediate  Endotheliomata. 

The  malignant  melanoma  bears  the  same  relationship  to  the  pigmented  wart, 
as  the  maUgnant  epithelioma  does  to  the  papilloma.  That  is  to  say,  the  mahgnant 
cells  are  recognised,  not  because  they  invade  healthy  tissue,  a  statement  which 
is  impossible  to  make  in  the  case  of  the  melanoma,  but  because  the  tumour  cells 
vary  very  much  in  size,  exhibit  marked  nuclear  and  nucleolar  activity,  and  in  both 
cases  pseudo -parasitism  of  the  nucleolus  is  discernible.  I  consider  that  the  so-called 
malignant  melanoma  is  exactly  analogous  to  that  case  of  malignant  pigmented 
epitheUoma  described  in  Chapter  XLV,  and  from  which  Plates  43  and  44  are  taken. 
In  both  instances,  the  type  of  malignancy  is  what  might  be  called  the  pseudo-parasitic 


ROLE    PLAYED   BY   ENDOTHELIAL    CELL.  579 

type,  in  contradistinction  to  that  type  in  which  the  cells  arc  of  a  distinctly  embryonic 
character — the  embryonic  type,  or  what  I  have  described  above  as  embryonic 
activity.  The  embryonic  epithehal  cell  resembles  very  closely  that  cell  which 
constitutes  the  basal  layer  of  the  epidermis,  and  of  which  the  rodent  ulcer  consists, 
but  what  are  exactly  the  characteristics  of  the  embryonic  endothelial  cell,  is  not 
so  certain.  I  am  incUned  to  the  view  myself,  that  the  embryonic  endotheUal  cell 
is  a  spindle  cell,  and  that  it  gives  rise  on  the  one  hand  to  endothelial  cells,  and  on 
the  other  hand  to  connective-tissue  cells  which  form  the  support  of  the  endothelial 
cells,  and  ultimately  become  the  walls  of  the  vessels.  If  correct,  an  analogy  would 
exist  between  the  endothehal  and  connective-tissue  cells  such  as  exists  between 
the  epidermis  and  its  appendages. 

The  first  section  taken  from  Case  92  is  made  up  of  what  I  take  to  be  embryonic 
endothelial  cells,  before  they  have  become  differentiated  into  endothelial  cells  and 
connective-tissue  cells.  This  case  I  regard  very  nuich  in  the  same  light  as  I  do  a 
case  of  mixed  epidermic  and  appendicular  epithelioma. 

The  spindle  and  round-celled  sarcomata  probably  arise  from  the  mature 
endothelial  cells  which  have  become  apportioned  to  form  connective-tissue  cells, 
and  those  cells  which  form  the  walls  of  vessels. 

1  Uima  (1896),  "  Histopathology  of  the  Dis.  of  the  Skin."     Trans,  by  Korman  Walker. 

W.  Clay.     Edinburgh. 

2  Kyrle  (1913),  "  Archiv.  f.  Derm.  u.  Syph.,"  cxviii,  319. 

3  Whitfield  (1900),  "  Brit.  Journ.  o£  Derm.,"  xii,  267. 

*  McDonagh  (1912),  "  Brit.  Journ.  of  Derm.,"  xxiv,  8.5. 
=  Sachs  (1903),  "  Archiv.  f.  Derm.  u.  Syph.,"  Ixvi,  101. 
«  Bauer  (189.5),  "  Virchow's  Archiv.,"  oxlii,  407. 
'  Delbanco  (1896),  "  Monat.  f.  prakt.  Dermat.,"  xxii,  105. 
"  Kromayer  (1890),  "  Dermat.  Zeitschr.,"  iii,  263. 

»  Gilchrist  (1899),  "  Journ.  of  Cutan.  and  Genito-Urinary  Dis.,"  xvii,  117. 
1"  Audry  (1900),  "  Monat.  f.  prakt.  Dermat.,"  xxx,  409. 


CHAPTER  XLVIII. 

THE  ROLE  PLAYED  BY  OTHER  CELLS  IN  INFLAMMATION,  AND  THEIR 
PROBABLE   RELATIONSHIP  TO  MALIGNANT  DISEASE. 

Introduction. 

The  other  cells  which  we  have  to  consider,  are  the  polymorphonuclear  leucocytes, 
the  basophile  leucocytes,  the  eosinophile  leucocytes,  and  the  connective-tissue 
cells.  All  these  cells  play  a  more  or  less  insignificant  part  in  chronic  inflammation. 
They  do  not  form  growths  of  their  own,  with  the  exception  of  the  connective-tissue 
cell,  therefore  no  relationship  exists  between  them  and  malignant  disease. 

Phagocytosis. 

The  mere  fact  that  the  polymorphonuclear  leucocyte  is  not  much  in  evidence 
in  chronic  inflammation,  should  go  far  to  lessen  the  importance  of  phagocytosis, 
for  surely,  the  more  chronic  the  lesion,  the  greater  the  call  upon  the  host's  pro- 
tective capacity.  Hence  if  phagocytosis  is,  as  many  observers  assert,  the  host's 
chief  means  of  ridding  himself  of  the  parasites,  surely  there  should  be  m5T:iads 
of  them  in  granulomata.  In  granulomata  the  polymorphonuclear  leucocyte  is 
outnumbered  by  the  lymphocyte,  in  which  is  incorporated  the  host's  main  protective 
weapon. 

P<ilymorphonuclear  leucocytes  contain  tiny  granules,  which  are  distinctly 
acidophile,  but  still  more  important  is  the  fact  that  these  granules  give  oxydase 
reactions. .  My  own  opinion  is,  that  phagocytosis  is  quite  a  secondary  phenomenon, 
for  reasons  which  are  given  in  Chapter  XXXI.  What  appears  to  happen  is,  that  the 
parasites  are  first  killed  by  the  circulating  lipoid-globulin,  and,  when  dead,  they  are 
removed  by  the  polymorphonuclear  leucocytes.  The  granules  probably  contain 
a  lipoid-globuUn  substance,  which,  when  activated  by  the  oxydases  attached  to  it, 
will  attract  and  adsorb  the  dead  bacteria. 

Here  are  two  other  proofs  in  favour  of  phagocytosis  being  only  of  secondary 
importance. 


ROLE    TLAYEI)    BV    POLYMORPHONUCLEAR   LEUCOCYTE.  581 

Certain  drugs  are  sometimes  prescribed  in  certain  infections,  to  produce  a 
hyperleucocytosis  (polymorphonuclear  leucocytes)  and  fever. 

In  the  case  of  sj'philis,  injections  of  nucleic  acid  have  undoubtedly  a  very 
beneficial  action  on  the  lesions,  due  to  the  fever,  since  the  adsorptive  power  of  the 
host's  protective  substances  is  much  greater,  when  the  temperature  is  39°  C.  or 
40°  C,  than  it  is  when  it  is  only  31°  C. 

Phagocytosis  plays  no  part  in  the  host's  protective  machinery  against  syphilis. 
Other  chemical  substances  may  be  injected,  and  they  will  cause  fever  but  no  hyper- 
leucocytosis, with  beneficial  results,  hence  it  is  the  fever  which  is  the  important 
point,  not  the  hyperleucocytosis. 

In  pyogenic  infections,  the  greater  the  quantity  of  polymorphonuclear  leuco- 
cytes, the  greater  the  quantity  of  pus.  When  pus  forms,  we  let  it  out,  as  we  are 
told  to  look  upon  pus  as  a  collection  of  polymorphonuclear  leucocytes  which  have 
done  their  work,  and  are  now  dead.  Many,  if  not  most,  of  the  polymorjjhonuclears 
in  pus  are  not  dead,  and  the  majority  of  those  that  are,  the  cocci  themselves  have 
killed.  We  let  the  pus  out  first,  because  it  swarms  with  cocci,  which  are  living  at 
the  expense  of  the  leucocytes  ;  and  secondly  because  pus,  owing  to  its  strong  proteo- 
lytic action,  destroys  the  healthy  tissues  around.  Although  the  formation  of  pus 
is,  in  a  sense,  a  sign  of  the  patient's  protective  power,  the  same  ratio  between  the 
quantity  which  is  formed  and  the  severity  of  the  infection,  as  is  seen  when  the 
lymphocyte  is  attacked,  does  not  exist.  The  more  lymphocytes  that  are  formed 
in  an  infection,  the  cause  of  which  stimulates  their  j^roduction,  the  less  the  number 
of  parasites  that  will  be  found  in  the  lesion  formed  thereby  ;  and,  however  large 
the  lymjihatic  gland  is,  we  do  not  advise  its  removal.  If  phagocytosis  were  the 
host's  chief  mode  of  protecting  himself,  surely  the  more  polymorphonuclear 
leucocytes  which  he  formed,  the  fewer  would  he  the  number  of  the  parasites, 
as  is  the  case  when  the  lymphocyte  is  called  up,  but  it  is  not  actually  so. 

One  other  point.  In  pyogenic  infections,  an  enlargement  of  the  regional 
lymphatic  glands  usually  occurs.  If  the  phenomenon  of  phagocytosis  were  so 
exceedingly  important,  one  would  expect  to  find  the  enlargement  of  the  lymphatic 
gland  due  to  an  engorgement  of  polymorphonuclear  leucocytes,  but  we  do  not.- 
On  the  contrary,  if  such  a  lymjjhatic  gland  is  examined  before  suppuration  sets  in, 
it  will  be  found  that  the  enlargement  is  due  to  an  increase  in  formation  of  l3'mpho- 
cytes,  and  the  endothehal  cells  will  be  found  to  be  exceptionally  busy  in  the 
production  of  lymphocytes. 

From  this  it  follows,  that  even  in  infections  where  phagocytosis  is  so  marked, 
the  lymphocyte  plays  a  role,  and  because  the  part  played  by  .the  lymphocyte 
is  less  advertised  than  that  played  by  the  polymoi-phonuclear,  it  has  been  missed 


582  BIOLOGY   OF  INFLAMMATION  AND   MALIGNANT  DISEASE. 

or  misinterpreted.     The  lymphocyte  is,  in  my  opinion,  the  patient's  chief  protective 
cell,  and  I  regard  phagocytosis  as  being  of  quite  secondary  importance. 

Polymorphonuclear  Leucocyte. 

The  polymorphonuclear  leucoc}i;e  develops  from  a  myelocyte,  and  the  myelocyte 
from  a  myeloblast ;  it  is  an  end  phase,  and  it  is  formed  in  the  bone-marrow.  The 
plasma  cell  may  be  regarded  as  the  end  phase  of  a  lymphocyte,  but  there  is  a  very 
considerable  difference  between  the  plasma  cell  and  the  pol3anorphonuclear  leucocyte. 
Leave  aside  the  protoplasm,  and  compare  the  nuclei.  The  nucleus  of  a  plasma  cell 
is  very  much  alive ;  it  is  regular  in  outline,  its  chromatin  stains  deeply,  and, 
what  is  still  more  to  the  point,  it  contains  a  nucleolus.  The  nucleus  of  a  plasma 
cell  may  exist  perfectly  well  alone,  without  its  surrounding  protoplasm ;  it  may 
divide  and  subdixdde,  its  nucleolus  may  develop  pseudo-parasitically, — in  short, 
the  plasma  cell  may  be  the  origin  of  a  malignant  development. 

The  nucleus  of  the  polymoi-phonuclear  leucocyte  is  irregular,  its  chromatin 
stains  badly ;  it  has  no  nucleolus,  it  cannot  exist  alone,  nor  imdergo  under  further 
transformation,  except  disintegration,  and  yet  we  are  to  look  ujion  phagocytosis  as 
being  the  most  important  protective  process. 

Owing  to  the  fact  that  the  polymorphonuclear  leucocyte  is  formed  in  the  bone- 
marrow,  itwilLfoUow  that,  before  it  reaches  its  destination,  it  must  travel  the  round 
of  the  blood  stream.  Hence,  if  the  infection  happens  to  be  one  which  calls  for  these 
leucocytes,  an  examination  of  the  blood  will  reveal  a  hyperpolymorphonuclear  leuco- 
cytosis.  In  the  case  of  the  lymphocyte,  it  is  formed  in  situ,  in  the  lymphatic  glands, 
spleen,  bone-marrow,  etc.  As  the  first  three  positions  can  usually  form  enough 
to  combat  the  infection,  and  as  the  lymphoe3i:es  formed  there  remain  where  they  are 
formed,  an  examination  of  the  blood  will  not  reveal  the  part  which  the  lymphocyte 
is  playing,  consequently  it  has  followed  that  all  attention  has  been  paid  to  the  poly- 
moi-phonuclear  leucocyte,  and  none  to  the  lymphocyte. 

Apart  from  the  mere  local  action  of  a  lymphocyte,  which  is  partly  to  fonn 
plasma  cells,  its  main  action  is  to  charge  the  serum  with  protective  lipoid-globulins, 
hence  the  reason  why  there  is  no  necessity  for  the  lymphocytes,  which  are  formed 
in  the  lymphatic  glands  and  spleen,  to  leave  the  place  of  their  birth. 

Basophile  Leucocyte. 

There  are  two  kinds  of  basophile  leucocj'tes — one  is  called  the  blood 
basophile,  and  the  other  the  tissue  basophile.  The  blood  basophile  is  developed 
from    a   myelocyte,  which  in   turn   is    born    of    a   myeloblast,    hence   it    is   very 


HOLE    PLAYED    BY   BASOPIIILE    LEUCOCYTE.  583 

closely  related  to  the  polymorphonuclear  leucocyte.  The  blood  basophile  is  an  end 
cell ;  its  nucleus  is  irregular,  and  it  does  not  contain  a  nucleolus.  It  is  a  more  higlily 
organised  cell  than  the  polymorphonuclear  leucocyte  ;  the  protoplasm  is  more 
markedly  granular,  the  granules  are  basophilic,  and  they  give  very  marked  oxydase 
reactions.  As  the  granules  are  so  rich  in  oxydases,  one  is  tempted  to  suggest  that 
the  function  of  a  blood  basophile  is  to  be  a  sort  of  reserve  complement.  In  other 
words,  an  activator  of  the  adsorptive  action  of  the  hpoid-globuhn  in  the  serum, 
held  in  reserve. 

The  tissue  basophile,  or  mast  cell,  is  commonly  said  to  arise  from  a  connective- 
tissue  cell,  but  I  am  tolerably  certain  that  it  can  originate  from  a  lymphocyte,  or 
directly  from  an  endothelial  cell.  If  true,  then  the  finding  of  those  small  granular 
cells — which  I  frequently  came  across  when  examining  tissue  in  vivo  and  which  are 
depicted  in  Plate  19  (15,  16),  will  be  explained.  These  small  granular  cells,  the 
granules  of  which  show  a  greater  affinity  for  methylene  red,  are  possibly  embrj'o 
mast  cells.  I  should  not  be  surprised  if,  in  later  years,  it  is  proved  that  the  mast 
cell  develops  from  the  lymphocyte  or  the  endotheUal  cell  only.  The  connective- 
tissue  cell  alwa3's  strikes  me  as  being  a  more  or  less  insignificant  cell.  Somehow  or 
other,  I  cannot  regard  its  action  as  other  than  mechanical,  namely,  to  form  a  barrier, 
and  to  hedge  in  the  local  infective  process.  It  is  difficult  to  imagine  a  connective 
tissue  cell  giving  rise  to  a  highly  organised  cell  hke  the  tissue  basophile,  when  we  know 
that  the  most  important  function  of  connective  tissue  is  to  form  collagen  and  elastin. 
The  tissue  basophile  in  its  early  stages,  i.e.,  after  the  small  granular  form  just  referred 
to,  is  round ;  the  nucleus  is  also  perfectly  spherical,  and  it  contains  a  nucleolus, 
ilorphologically,  the  cell  resembles  a  plasma  cell,  with  the  exception  that,  in  the 
case  of  the  basophile,  the  nucleus  is  in  the  centre  of  the  cell. 

As  the  cell  becomes  more  and  more  mature,  the  nucleus  becomes  insignificant, 
and  eventually  disappears,  the  cell  varies  in  shape  and  becomes  angular,  the 
granules  become  more  distinct,  and  separate  from  one  another,  and  then  either 
a  portion  of  the  protoplasm  of  the  cell  breaks  away  en  masse,  or  the  granules  become 
liberated  one  by  one.  In  any  case,  the  granules  become  free.  Sometimes  the  cell 
does  not  break,  but  when  it  reaches  the  basal  layer  of  the  epidermis,  it  sends  pseudo- 
podic  processes  between  the  cells.     The  granules  are  capable  of  movement. 

With  rongalit  white,  the  mast  cell  granules  stain  blue,  which  proves  that  they 
contain  oxygen. 

This  oxygen  is  in  the  form  of  a  peroxydase,  since  the  granules  stam  with 
benzidine  and  hydrogen  peroxide.  A  like  result  may  also  be  obtained  by  treating 
the  sections  with  paraphenylenediamine  tartrate  (ursol-tartrate)  and  hydrogen 
peroxide. 


584  BIOLOGY    OF   INFLAMMATION   AND    MALIGNANT   DISEASE. 

The  granules  stain  red  with,  polychrome  methylene  blue,  because  of  their  very 
strong  reducing  action,  which  picks  out  the  methylene  red  part  of  the  stain  and 
refuses  the  methylene  violet. 

This  action  is  not  due  to  the  fact  that  the  granules  are  basic,  and  therefore 
prefer  acid  stains,  because  the  granules  are  absolutely  basophilic,  and  will  stain 
with  no  acid  dyes. 

With  pyronin  and  methyl  green,  in  some  cases  the  mast  cells  stain  green  with 
the  methyl  green,  but  far  more  usually  they  stain  with  the  pyronin  either  red, 
orange,  or  brown. 

When  the  mast  cells  stain  with  methyl  green,  as  I  have  seen  them  do,  in  a  case 
of  sporotrichosis,  they  are  invariably  round,  stain  homogeneously,  and  show  only  a 
few  very  fine  granules.  When  the  mast  cells  stain  red  with  pyronin,  they  are 
usually  found  in  the  region  of  the  epidermis  and  in  great  numbers,  as,  for  instance, 
in  Urticaria  pigmentosa. 

In  all  forms  of  chronic  inflammation,  the  granules  usually  stain  orange,  and 
in  acute  fatal  inflammation  they  stain  brown. 

Mast  cells  contain  free  oxygen  and  oxygen  ferments,  and  in  this  respect 
resemble  the  nuclei  of  cells,  but,  in  the  former,  the  oxygen  content  is  very  much  more 
marked. 

Nuclei  show  a  strong  affinity  for  methyl  green,  owing  to  the  nucleic  acid 
radicle,  therefore  it  is  possible  that  those  mast  cells  which  stain  green  are  less  active 
than  those  which  stain  with  pyronin,  and  that  the  granules  contain  some  acid 
radicle  analogous  to  nucleic  acid. 

In  those  granules  which  stain  with  pyronin,  although  the  oxygen  may  be,  and 
is  present  in  large  quantities,  both  free  and  in  the  form  of  peroxydases,  there  must 
be  some  substance  which  has  very  powerful  reducing  properties,  and  which 
prevents  the  grainiles  from  staining  with  methyl  green.  A  powerful  reducing  sub- 
stance is  also  to  be  found  in  red  blood  corpuscles,  which  likewise  contain  free  oxygen 
and  peroxydases;  but  even  then  they  do  not  stain  with  methyl  green.  Red  blood 
corpuscles,  on  the  other  hand,  prefer  acid  stains,  probably  on  account  of  the  basic 
globin,  so,  although  there  is  a  similarity  between  mast  cell  granules  and  red  blood 
corpuscles,  they  contain  proteins  which  are  entirely  different.  What  the  protein 
is  in  the  mast  cell  granules,  is  not  quite  clear. 

The  granules  are  insoluble  in  alcohol,  ether,  and  chloroform.  They  are  soluble 
in  the  chlorides  of  sodium,  potassium,  ammonium,  and  calcium  ;  the  sulphides  of 
potassium,  barium,  and  ammonium ;  the  sulphates  of  sodium,  magnesium,  and 
ammonium  ;  the  acetates  of  sodium,  and  ammonium;  potassium  iodide,  potassium 
ferro-  and  ferricyanide,   and  ammonium  oxalate.     The  granules  are  also  soluble 


ROLE  PLAYED  BY  BAROPHILE  LEUCOCYTE.  585 

in  alkaline  salts  and  alkalis,  such  as  the  phosphates,  carbonates,  bicarbonates 
and  biborates  of  sodium  and  potassium,  and  in  aqua  calcis.  They  are  insoluble 
in  mineral  and  organic  acids  as  hydrochloric,  nitric,  sulphuric,  phosphoric,  salicylic, 
acetic,  trichloracetic,  lactic,  oxalic  and  pepsin  hydrochloric  acid. 

Alum,  calcium  bisulphide,  and  the  salts  of  oxalic  and  citric  acids  do  not  dis- 
solve the  granules.  The  salts  of  the  heavy  metals  do  not  dissolve  the  graiuiles, 
for  example,  copper  and  zinc  sulphates,  zinc  and  mercuric  chlorides,  and  lead 
acetate. 

The  mast  cell  granules  were  considered  for  a  long  time  to  contain  mucin,  but 
Unua^  has  clearly  shown  that  such  is  not  the  case.  Mucin,  for  instance,  swells  in 
water,  the  mast  cell  granules  partly  dissolve.  Mucin  is  not  dissolved  by  weak 
solutions  of  neutral  salts,  while  the  mast  cell  granules  are.  Mast  cell  granules  are 
insoluble  in  alcohol,  pepsin  hydrochloric  acid,  and  tannin ;  while  mucin  is  soluble 
in  these  reagents ;  mucin  swells  in  potassium  dichromate,  while  the  granules  dissolve 
therein.  In  saturated  solutions  of  sodium  chloride  and  sulphate,  mast  cell  granules 
dissolve,  but  not  so  mucin. 

As  Unna  ^  says  :  „  Trofz  dieser  nicht  unerheblichen  Differenzen,  scJiliesst  sich 
die  Mastzellenkornung  von  alien  Eiweissstoffen  am  engsten  den  Mucinen  und  Mucoiden 
an." 

Micro-chemistry  is  yet  in  its  early  infancy,  and,  unless  we  are  careful,  we  shall 
make  the  same  mistakes  as  others  have  made,  who  have  dealt  with  the  chemistry 
of  substances  they  have  abstracted  from  this  or  that  organ.  The  result  has  been 
that,  so  far  as  proteins  are  concerned,  their  number  is  legion,  while  in  reality  it  is 
more  probable  that  there  are  two,  if  not  only  one  protein,  the  difference  being 
brought  about  by  the  varied  chemical  substances  with  which  they  are  bound  up,  and 
which,  moreover,  are  extremely  difficult  to  remove.  When  Unna  foimd  that  there 
was  globulin  in  the  nucleolus,  for  instance,  he  rightly  admitted  that  it  differed  in 
many  details  from  native  globulin.  The  difference  is  not  due  to  the  globulin  itself, 
but  to  the  presence  of  a  lipoid  with  which  it  forms  a  colloidal  complex  or  adsorption 
compound.  So  stable  is  this  compound,  that  ordinary  lipoid  solvents  will  not 
separate  off  the  lipoid  fraction  ;  therefore,  when  Unna  went  to  the  trouble  of  treating 
his  specimens  with  ether  and  alcohol,  he  did  not  remove  all  the  lipoid  material  as  he 
thought  he  had  ;  hence  he  missed  the  fact  that  he  was  dealing  only  with  ordinary 
globulin,  which  was  alloyed,  so  to  speak.  Because  the  alloy  behaved  differently 
to  reagents,  Unna  thought  that  the  globulin  itself  must  be  different. 

As  globulin  may  have  substances  attached  to  it,  so  may  nmcin,  thei-efore  it  is 
highly  probable  that,  mucoids  are  complex  bodies,  of  which  the  base  is  nuicin. 

Mucoids  are  rich  in  oxygen,  distinctlv  acid  in  character,  are  soluble  in  alkalis 


580  BIOLOGY   OF   INFLAMMATION   AND   MALIGNANT   DISEASE. 

and  also  in  acids,  when  in  excess,  even  in  acetic  acid,  which  has  a  particularly 
powerful  precipitating  action  upon  mucin. 

The  most  important  feature  of  mast  cells  is  that  they  will  not  stain  with  acid 
dyes,  therefore  there  is  probably  an  acid  in  the  granules,  analogous  to  the  nucleic 
acid  in  nuclein,  and  to  the  chondroitin  sulphuric  acid  in  cartilage. 

The  analogy  becomes  closer,  when  it  is  remembered  that  some  mast  cells  do 
stain  with  methyl  green,  a  dye  which  is  well  known  for  its  affinity  for  nucleic  acid 
and  chondroitin  sulphuric  acid. 

Probing  the  analogy  still  further,  we  find  that  chondromucoid^  is  mucin  plus 
chondroitin  sulphuric  acid,  a  substance  which  is  characterised  by  containing 
2  ■  42  per  cent,  of  sulphur. 

All  mucoids  have  two  points  in  common.  The  one, that  they  contain  sulphur; 
the  other,  that  the  sulphur  can  be  obtained  as  an  acid. 

Tendomucoid'^  contains  2 "  33  per  cent,  of  sulphur,  which  can  be  separated  oS 
as  glucothionic  acid. 

Nucleic  acid  does  not  exist  in  the  nucleus  as  a  free  acid.  It  is  firmly  bound  up 
with  the  protein  as  nuclein,  to  which  it  imparts  an  acid  character.  This  is  likewise 
the  case  with  chondroitin  sulphuric  acid  and  glucothionic  acid. 

Most  mast  cells  stain  with  pyronin,  and  readily  with  the  methylene  red  fraction 
of  either  borax  methylene  blue  or  polychrome  methylene  blue,  therefore  the  granules 
contain  a  reducing  agent,  the  action  of  which  is  very  pronounced.  Mucin  and 
mucoids,  or,  as  they  are  sometimes  called  collectively,  glycoproteins,  contain  a 
powerful  reducing  carbohydrate  molecule,  which  is  probably  in  the  form  of  a 
polysaccharide. 

Mast  cell  graiuiles  reduce  Fehling's  reagent;  and  on  leaving  sections  for  forty-eight 
hours  at  37°  C.  in  a  solution  of  0'5  per  cent,  potassium  hydroxide  in  90  per  cent, 
alcohol,  and  then  innnersing  them  in  a  2' 5  per  cent,  solution  of  dimethyl  para- 
minobenzaldehyde  in  1  per  cent,  hydrochloric  acid,  the  granules  stain  a  carmine 
colour,  which  indicates  the  presence  of  an  aminohexose  or  glucosamine,  as  it  is 
called. 

From  this  it  follows,  that  the  reducing  action  of  the  mast  cell  granules  is  due 
to  a  carbohydrate  molecule,  therefore  the  granules  contain  both  an  acid  and  a 
carbohydrate,  and,  in  addition,  free  oxygen.  What  the  base  is,  is  by  no  means 
certain.  It  may  be  a  simple  albumin,  or  it  may  not  be  a  protein  at  all,  and  it  is 
exceedingly  doubtful  \\hether  micro-chemistry  will  solve  the  question,  as  no  observer 
will  ever  be  able  to  be  sure  that  the  associated  fractions  of  the  large  molecule  have 
been  removed. 

The  function  of  a  mast  cell  is  to  both  give  oflt  ox3'gen  and  to  activate  oxygen, 


ROLE    PLAYED    BV    EOSINOPHILE   LEUCOCYTE.  587 

and,  where  mast  cells  are  most  required,  the  reducing  action  of  the  granules  is  greatest, 
therefore  there  must  be  some  association  between  the  oxygen  and  the  carbohydrate 
molecules.  In  tissues  where  mast  cells  are  least  recjuired,  the  reducing  action  is 
so  small  and  is  so  overshadowed  by  the  sulphuric  acid  radicle,  tliat  the  cells  stain 
with  methyl  green.  Hence  the  explanation  of  the  variations  in  colour  to  be  met 
with  in  mast  cell  granules,  when  stained  with  the  pyroniii  methyl  green  mixture — 
first,  green,  owing  to  predominance  of  sulphuric  acid  radicle  ;  then  red,  owing  to 
predominance  of  carbohydrate  radicle,  which  changes  to  orange  and  brown  as  the 
reducing  agent  increases. 

Mast  cells  are  to  be  found  most  abundantly  in  pigmentary  affections,  therefore 
there  must  be  a  close  relationship  between  mast  cells  and  pigment  formation.  The 
formation  of  pigment  is  an  oxydase  reaction,  a  tyrosine-tyrosinase  reaction.  Mast 
cell  granules  are  extraordinarily  rich  in  oxydases,  hence  they  may  be  a  ready  means 
of  supply  for  this  reaction.  After  all,  the  formation  of  pigment  is  a  protective 
phenomenon.  Mast  cells  are  also  found  in  lesions  where  not  onh'  could  the  forma- 
tion of  pigment  not  take  place,  but  where  it  would  be  useless  if  it  could,  hence  the 
granules  must  have  also  another  function. 

Broadly  speaking,  the  severer  the  infection,  the  more  active  do  the  mast  cells 
become.  In  severe  infections,  or  in  the  late  stages  of  a  very  chronic  infection, 
complement  may  be  absent,  or  very  markedly  diminished.  In  Chapter  X.  I 
showed  that  complement  was  probably  the  oxydase  part  of  the  lipoid-globulin, 
and  also  that  the  adsorptive  action  of  the  lipoid-globulin  disappeared,  if  no  oxydase 
was  present.  Mast  cells  granules,  then,  possibly  act  as  a  reserve  supply  of  com- 
plement, or  of  the  ferment  which  the  lipoid-globulin  requires  to  activate  its 
adsorptive  action. 

EosiNOPHiLE  Leucocyte. 

This  form  of  leucocyte  develops  from  a  myelocyte,  and  this  from  a 
myeloblast,  similar  to  the  basophile,  and  it  likewise  bears  a  close 
relationship  to  the  polymorphonuclear  ]eucoc3^te.  The  nucleus  is  irregular,  usually 
bipartite,  but  there  is  no  nucleolus.  The  protoplasm  is  granular,  and  these  granules 
ultimately  become  loose,  as  do  those  of  the  basophiles.  The  granules  are  refractile. 
They  have  a  marked  preference  for  acid  dyes,  such  as  eosin,  acid  fuchsin,  and 
safranin,  but  they  will  stain  with  pyronin,  which  is  a  basic  dye.  This  is  probably 
due  to  the  fact  that  the  granules  have  a  reducing  action.  The  granules  synthesise 
indophenol,  hence,  like  the  basophile  granules,  they  are  rich  in  oxydases.  The  action  of 
the  eosinophiles  is  almost  certainly  the  same  as  that  of  the  basophiles,  but  whv 
the  granules  in  the  one  case  should  be  acidophilic,  and  in  the  otiior  case  busopliilic, 
is  by  no  means  clear. 


588  BIOLOGY    OF   INFLAMMATION   AND   MALIGNANT   DISEASE. 

The  granules  of  the  polymorphonuclear  leucocyte  are  generally  regarded  as 
neutral,  hence  it  is  often  called  the  neutrophile  leucocyte.  Strictly  speaking,  this  is 
by  no  means  the  case,  as  in  some  instances  the  granules  are  distinctly  basophilic, 
while  in  other  instances  they  are  acidophilic.  They  are  more  often  acidophilic  than 
basophilic.  Occasionally,  it  is  possible  to  see  intermediate  stages,  so  to  speak, 
between  the  neutrophile  leucocyte,  with  the  basophile  on  the  one  hand,  and  with 
the  eosinophOe  on  the  other  hand.  The  two  most  striking  differences,  to  my  mind, 
between  the  neutrophile  and  the  basophile  and  eosinophile,  are,  first,  the  granules 
are  not  so  developed  ;  and,  secondly,  the  nucleus  is  more  degenerate.  Broadly 
speaking,  neither  basophiles  nor  eosinophiles  are  called  upon,  unless  the  condition 
is  chronic.  They  both  appear  to  have  more  vitality  than  the  neutrophile,  and  still 
we  are  expected  to  regard  the  polymorphonuclear  leucocyte  as  man's  saviour 
against  disease. 

Connective-Tissue  Cell. 

The  main  points  about  a  connective-tissue  cell  have  already  been  discussed, 
and  its  function  has  been  mentioned  {inde  Chapter  XL VI),  but  there  are  one  or  two 
other  remarks  which  may  be  made  about  this  cell.  The  connective-tissue  cell, 
like  the  epithelial  cell  is  one  of  the  body's  formed  cells — ^that  is,  it  becomes  differen- 
tiated fron:  the  mesoblast  in  very  early  embryonic  life,  and  can  only  develop  from 
a  connective-tissue  cell.  This  being  so,  it  might  be  reasonable  to  expect  that  the 
connective-tissue  cell  has  the  same  vagaries  as  an  epithelial  cell.  So  it  has.  The 
nucleus  of  a  connective-tissue  cell  is  regular.  Its  chromatin  stains  well  ;  it  has 
one  or  more  nucleoli,  and  division  and  subdivision  take  place,  to  form  new  connective 
tissue  cells. 

Epithelial  cells  degenerate  and  form  eleidin,  .keratohyalin  and  keratin,  substances 
which  mainly  consist  of  amino-acids.  Connective-tissue  cells  degenerate,  and  form 
collagen  and  elastin,  substances  again  which  mainly  consist  of  amino-acids. 

Epithelial  cells  may  form  a  new  growth,  and  the  new  growth  may  be  malignant. 
The  same  with  the  connective-tissue  cells.  A  new  growth  of  connective-tissue  cells 
is  called  a  fibroma  ;   if  it  is  malignant,  it  receives  the  name  of  sarcoma. 

We  know  that  there  is  a  form  of  epithelioma,  the  cells  of  which  are  so  embryonic 
that  it  is  impossible  to  say  whether  the  epithelioma  is  an  epithelioma  which  has 
arisen  from  cells  destined  to  form  the  stratum  malpighii,  or  from  cells  destined 
to  form  one  or  other  of  the  appendages.  Epitheliomata,  which  arise  from  epithelial 
cells  more  embryonic  still,  exhibit  the  phenomenon  of  what  is  best  called  embryonic 
activity — e.g.,  rodent  ulcer. 

A  relationship  exists  between  muscular  tissue  and  connective  tissue,  analogous 


ROLE   PLAYED    BY   CONNECTIVE- TLSSUE   CELL.  589 

to  that  which  exists  between  epithelial  appendicular  tissue  and  epithehal  rete  tissue. 
Of  epithelial  appendages  there  are  three — hair  folheles,  sebaceous  glands,  and  sweat 
glands.  There  are  also  three  kinds  of  muscular  tissue — unstriped,  striped,  and 
cardiac. 

The  embryonic  cell  of  the  epithelial  appendages  is  also  the  embryonic  cell  of 
the  stratum  malpighii.  The  embryonic  cell  of  connective  tissue  is  also  the 
embryonic  cell  of  muscular  tissue. 

In  the  one  case,  a  new  growth  of  the  embryonic  cell  is  called  a  malignant  epi- 
thelioma ;  and  in  the  other,  a  sarcoma. 

In  the  epithelial  chain,  intermediate  links  exist ;  so  they  do  in  the  connective 
tissue  chain. 

The  new  growth  which  corresponds  to  the  mixed  epidermic  appendicular  growth 

is  the  leiomyoma.    In  some  of  these  new  growths  of  the  corium,  it  is  quite  impossible 

to  say  whether  the  cells  constituting  the  growth    are  connective-tissue  cells    or 

muscle  cells.     Some  of  these  leiomyomatous  growths  show  a  marked  tendency 

to  recur,  if  removed,  which  strongly  suggests  a  position  near  the  embryonic  activity 

end  of  the  chain. 

Summary  of  Part  II. 

To  make  the  subject  of  this  second  part  of  the  book  as  clear  as  possible,  I  will 
attempt  to  give  a  short  summary  thereof. 

The  cells  discussed,  with  the  exception  of  the  polymorphonuclear  leucocyte, 
the  eosinophile  cell,  and  the  mast  cell,  can  divide  and  multipl^^ 

Such  cells  as  the  epithelial  cells,  endothelial  cells  and  connective-tissue  cells 
have  an  embryonic  history.  The  embryonic  epithehal  cell  is  a  spindle  cell,  which 
develops  fi-om  the  epiblast.  The  embryonic  endothelial  cell  and  connective-tissue 
cell  are  also  spindle  cells,  and  are  probabl}^  of  the  same  origin  ;  they  both  develop 
from  the  mesoblast. 

Should  a  new  growth  of  these  embryonic  cells  arise,  the  tumour  formed  may 
ulcerate,  spread,  and  tend  to  recur  on  removal.  This  phenomenon  may  be  best 
designated  as  embryonic  activity.  It  is  not  strictly  malignant,  since  metastases 
do  not  form,  and  the  cells  do  not  exhibit  nuclear  and  nucleolar  activity.  What 
causes  these  new  growths  to  arise  is  unknown. 

Passing  from  the  embryonic  cells,  we  come  upon  more  mature  cells.  The 
spindle-shaped  epithelial  cell  becomes  the  cubicle  cell  of  the  stratum  malpighii. 

The  spindle-shaped  mesoblastic  cell  becomes  on  the  one  hand,  an  endothelial 
cell,  and  on  the  other  hand  a  connective-tissue  cell.  A  new  growth  of  these  cells 
may  arise  ;    usually  they  are  quite  innocent,  but  on  the  other  hand,  the  cells  may 


590  BIOLOGY   OF   INFLAMMATION   AND    MALIGNANT   DISEASE. 

show  pronounced  nuclear  and  nucleolar  activity,  or,  in  other  words,  behave  pseudo- 
parasitically,  when  they  may  ulcerate,  recur  and  form  metastases.  This  pheno- 
menon is  best  designated  as  malignancy.  A  very  common  cause  of  the  multi- 
plication of  these  mature  cells  is  inflammation.  The  cells  multiply  to  protect  their 
host,  and  the  more  their  protective  capacity  is  taxed,  the  greater  the  likelihood 
that  they  will  develop  pseudo-parasitically.  Malignancy,  then,  is  probably  an 
end  result  of  chronic  inflammation,  or  even  of  acute  inflammation,  if  the  attacking 
force  and  the  response  offered  against  it,  are  of  a  sufficiently  powerful  nature, 
to  produce  nuclear  and  nucleolar  activity. 

Between  the  most  embryonic  cells  and  the  most  mature  cells,  various  other 
cells  are  to  be  met,  with  the  result  tliat  the  histological  characters  of  new 
growths  vary  enormously. 

It  would  appear  from  my  research  work  on  these  lines,  that  the  more  mature 
the  cell  was,  the  greater  the  probability  that  it  would  develop  malignantly,  if 
stimulated  to  do  so  ;  provided  that  its  maturity  ceased  before  it  began  to  decline. 
A  cell  from  the  stratum  corneum  is  more  mature  than  a  cell  from  the  third  layer 
of  the  stratum  malpighii,  but  the  more  horny  a  malignant  epithelioma  is.  the  less 
dangerous  it  is,  because  the  cells  attacked  have  surpassed  their  zenith  of  maturity, 
and  have  entered  upon  their  stage  of  dechne. 

1  Unna  (1913),  "  Biochem.  der  Haul."     G.  Fischer.     Jena. 

-  Abderhalden    (1911),  ''  Bioshem.  Handlexikon"'     iv,  149.     J.  Springer.     Berlin. 

'  Ibid.,  iv,  150. 


INDEX. 


Abadie's  sign  (insensibility  of  Tendo  achilhs) 

in  degenerative  myelitis,  247. 
Abderhaldcn's  pregnancy  test,  94. 
Abderhalden's  reaction,  nature  of,  258. 
Abderhalden's   test,    process   of    precipitation 

and  hydrolysis,  96. 

specifieity  apparent,  not  real,  95. 

and  haeiuolytic  system,  analogy  between 

method  of  action,  95. 

and   Wassermann    reaction,   comparison 

between,  98. 

Abdominal  viscera,  syphilis  of,  174. 

Abortion  of  syphilitic  macerated  foetus,  260. 

Abscess,  prostatic,  393. 

Acetic  acid,  as  fixing  reagent  in  staining  of 
syphilitic  specimens,  34. 

Achilles  tendon,  pain  in,  406. 

Acid,  increase  in  female  cell  during  fertilisation, 
17. 

Acid  fuchsin  staining,  Altmann's  method  of, 
26. 

— ■ syphilitic  specimens  with,  34. 

Acids,  various,  behaviour  of  protein  of  syphilitic 
bodies  and  granoplasm  in  presence  of,  39,  40. 

Acne  vulgaris,  following  salvarsan  injections, 
301. 

Acoine,  352. 

Adam's  cream,  350. 

Adenoma,  sebaceous,  518,  521. 

Adenomata,  true,  522. 

Adrenalin,  in  conjunction  with  salvarsan,  304. 

in  haemorrhagic  encephalitis,  184. 

injection,  in  prevention  of  cerebral  com- 
pression, 184. 

untoward  symptoms  of  salvarsan  checked 

by,  226. 

Adsorption,  definition  of,  25. 

exhibited  by  dyes,  25. 

Albumin  in  cerebro-spinal  fluid,  187,  189,  190, 
205. 

Albumin  and  globiiltn  contents  of  cerebro- 
spinal fluid  in  cerebro-spinal  syphilis,  189. 

Albumin  complexes,  503. 

Albuminuria,  so-called,  in'  generalisation  stage 
of  syphihs,  84. 


Albumoses,  degeneration  products  of  protein. 
88. 

nature  of,  38. 

products  of  proteins,  503. 

Unna's  classification  of,  38. 

Alcohol,  abstinence  from,  diminishes  incidence 
of  syphilis,  496,  498. 

as  fixing  reagent  in  staining  of  syphilitic 

organisms,  32. 

of  syphilitic  specimens,  addition  of 

acetic  acid  to,  34. 

in  treatment  of  phthiriasis,  477. 

Alcoholic  stains,  results  for  method  in  vivo,  27. 
Aleucaemia,  536,  541. 

cutis,  546. 

Alkalinity,  definite  standard  of,  maintained  by 

blood,  278. 
Alopecia  in  congenital  syphilis,  264. 

syphilitic,  137. 

Altmann's  method  of  acid  fuchsin  staining,  26.^ 
Amaurosis  following  salvarsan,  308. 
Amblyopia  (atoxyl),  origin  of,  157. 
Amboceptor,  dried,  handiest  form  for  use,  66. 
■ how  to  dissolve,  66,  437. 

nature  of,  78. 

Amino-acid  content  of  syphilitic  sera,  87,  88. 

• depressed  by  triglycerides,  90. 

diminution  in,  87,  88. 

•  increased  by  fatty  acids,  90. 

•  increased  by  formalin,  91. 

increased  by  salvarsan,  93. 

less  in  untreated  cases,  88. 

raised  by  barium  sulphate,  91. 

raised  by  salvarsan,  89. 

•  and  result  of  Wassermann  reaction,  no 

direct  ratio  between,  92. 
■ — —  value  in  antigen,  71. 
Amino-aoids,     action     on     ferric -ferricyanide 

mixture,  37. 

• action  on  potassium  permanganate,  37. 

• addition   to  sera,  effect  on  Wassermann 

reaction,  92. 

amphoteric,  90. 

giving  Berlin  blue  reaction,  38. 

mode  of  existence  in  serum,  88. 


592 


INDEX. 


Amino-aoids,  non-existent  in  syphilitic  bodies 

in  free  state,  38. 

strong  reducing  agents,  37. 

Amino   dorivates,   time   required   to    give    ofi 

nitrogen  by  various  kinds,  87. 
Araino-nitrogen,  decrease  in  syphilitic  sera,  92. 
Amino-plasma  cells,  22,  35,  533. 

appearance  in  fixed  specimens,  3G. 

in  in  vivo  specimens,  36. 

in  chronic  inflammatory  lesions,  36. 

in  syphilitic  material,  36. 

staining  of,  502. 

and  syphilitic  bodies,  points  of  resem- 
blance of  difference,  36,  37. 

Ammonia,  solution  of,  action  on  nuclei  of 
syphilitic  bodies  and  on  herring's  roe  com- 
pared, 42. 

Ammonium  sulphate,  solution  of,  action  on 
nuclei  of  syphilitic  bodies  and  on  herring's 
roe  compared,  44. 

Amphoterism,  73,  90. 

Amyloid  disease  supervening  upon  chronic 
interstitial  syphilitic  nephritis,  153. 

Anaemia,  pernicious,  syphilis  very  occasionally 
cause  of,  151. 

syphilitic,  changes  in  red  blood  cor- 
puscles only  occur  in,  150. 

. due   to   use   of   salvarsan,    present 

rarity,  150. 
Anaesthesia,  deep,  complement  destroyed  by, 

65,  80. 
Anal  syphilitic  infection,    inguinal    lymphatic 

glands  enlarged  in,  132. 
Analgesia  in  degenerative  myelitis,  247. 
Anaphylactic  reaction,  117. 
Anaphylotoxine,    second    dose    of    salvarsan 

acting  as,  224,  225. 
Andrewes,   F.   W.,   ash  analyses  of  syphilitic 

aortae  showmg  deficiency  in  calcium  salts, 

85. 

diminished  calcium  content  of  syphilitic 

aortae,  148. 

— —  lipoid    cell    degeneration,    in    syphilitic 

aortitis,  85. 
Aneurysm,  congenital  syphilitic,  267. 

following  invasion  by  syphilitic  organism, 

215. 

aortic,  in  subject  of  congenital  syphilis, 

148. 

— —  popliteal,  syphilitic,  comparatively  early 
occurrence  of ,  148. 

Angina,  Vincent's,  diagnosis  from  primary 
chancre  of  tonsil,  164,  165. 

Animals  inoculated  with  syphilitic  material 
failing  to  develop  initial  lesion,  121. 

non-toxic  efEeots  of  salvarsan  injections, 

295. 

Anions,  effects  on  adsorptive  powers  of  electro- 
negative and  electro-positive  dyes,  26. 


in     syphilitic 


for- 


Anions,  staining  action  of  p3Tonin  and  methyl 

green  faciUtated  by,  27. 
Antibodies,  effect  on  cerebro-spinal  fluid,  221. 

formation  of,  checked  by  salvarsan,  141. 

■  diminishes   immunity    to    syphilis, 

142. 
not  checked  by  mercurj',  141. 

function  of,  287. 

persistent    production,    with    persistent 

Wassermann  reaction,  196. 

production  of,  checked  by  treatment,  219. 

how  provoked,  221. 

Antibody,  complement  identical  with,  83. 

demonstration   by   complement   fixation 

test,  69. 

fixation   of   complement   by  Spirochaela 

pallida  in  presence  of,  61. 

identity  of,  76,  82. 

lipoid-globulin     particles 

sera  become,  82. 
■ — —    See  also  Reagin. 
Antigen,  71,  436. 

action  of  increased  by  addition  of 

malin,  72. 

addition  of  cholesterol  to,  73,  74. 

addition    to    syphilitic    serum    increases 

size  of  ultra-microscopic  particles,  82. 

amino-acid  value  in,  71. 

•  best  form  of,  65. 

■  cholestcrolised,  results  with,  257. 

does  not  keep  when  diluted,  74. 

— — -  foetal  syphilitic  liver  used  as,  69. 
■  from  different  strains  of  gonococcus, 

increase  of  colloidal  particle  in,  72. 

lipoid  of,  71. 

neither  specific  nor  absolutely'  necessary 

for  Wassermann  reaction,  73. 

reagin    and     complement,     mixture 

effect,  78. 

Antiluetin,  intramuscular  injections,  348. 
Antimony,  intravenous  injections  of,  349. 

treatment  with,  348. 

Antiseptics  in  gonorrhoea,  383. 
Anus,  Condylomata  lata  around,  176. 

Aortae,  syphiUtic,  diminished  calcium  content 

of,  85,  148. 
Aortitis,  syphilitic,  147. 

absence  of  calcareous,  plates  in, 

lipoid  cell  degeneration  in,  85, 

with   general   arteriosclerosis, 

148. 

with  lipoid  degeneration,  148. 

. — ■ — •  with    ordmary    arterio-sclerosis    in 

other  vessels,  148. 
Apes,  inoculation  with  syphilis,  1. 
Aphthous  ulcers,  diagnosis  from  female  chancre, 

254. 
diagnosis  of  primary  chancre  from,  134. 

syphilitic,  162. 


439. 


of, 


148. 
147. 
147, 


INDEX. 


593 


fluid 


m, 


and 


Aphrodisiacs,  479. 
Arghiine,  test  for,  46. 
Argyll-Robertson    pupil,    cerebro-spinal 
normal  in  cases  of,  186. 

in  degenerative  myelitis,  245. 

Argyrol  in  treatment  of  gonorrhoea,  384. 
Army,    diminution    of    venereal    diseases 

495. 
Arsacetm,  281. 
— — ■  action  judged  by  clinical  methods,  282. 

formula  of,  281. 

less  toxic  and  more  stable  than  atoxyl, 

281. 
— —  more  toxic  than  salvarsan,  281. 
Arsenic  action  as  catalyser,  290. 

on    border    line    between    metals 

non-metals,  277. 

Arsenic  of  salvarsan,  action  of,  278. 
Arsenic-fast,  trypanosomes  rendered,  284. 
Arsenic  receptors,  284. 
Arsenical  compounds,  treatment  by,  347. 

poisoning,  water  contammation  in,  296. 

Arseno-phenyl-glycine,  action  of,  280,  282. 

advantages  and  disadvantages  of,  282. 

formula  of,  282. 

Arterial  lesions  of  nervous  system,  201. 
Arteries,  congenital  syphilitic  disease  of,  267. 

syphilitic,  diseases  of,  content  of  cerebro- 
spinal fluid  in,  195. 

syphilitic  lesions  of,  147,  215. 

in  women  rare,  257. 

Arterio-solerosis,  general  in  syphilitic  aortitis, 
147,  148. 

generalised  syphilitic,  chronic  interstitial 

nephritis  usually  symptom  of,  153. 

of  ordinary  type  in  other  vessels,  accom- 
panying syphilitic  arterio-sclerosis,  148. 

Arteritis,  syphilitic,  how  ditferhig  from  other 

forms,  147. 
Arthigon,  442. 

Arthralgia,  treatment  of,  410. 
Arthritis,  adhesions  in,  411. 

gonococcal,  407. 

emaciation  and  loss  of  weight  in, 


173. 


173. 


followed    by    Arthritis    deformans, 


■  phlegmonous,  409. 

serofibrinosa,  408. 

treatment  of,  411,  456. 

- —  polyarticular,  409. 

simulating  tubercular  joints  in  congenital 

syphilis,  267. 

syphilitic,  172. 

diagnosis,  173.  ^   ' 

emaciation  and  loss  of  weight  in, 

172,  173. 
- — ■  syphilitic  and  gonococcal,  differentiation 

between  impossible,  173. 


Arthritis  dejormans  affecting  both  hip  joints, 
after  gonorrhoea  and  syphilis,  173. 

origin  of,  in  cases  of  syphilis,  172,  207. 

Arthritism  and  Induratio  jienis  plaslica,  475. 

Ascites,  chylous  and  pseudo-chylous,  fluid  from, 
181. 

congenital  syphililic  rare,  208. 

■  pseudo-chylous,  syphilitic,  180. 

Ascoli,  meiostagmine  reaction,  70. 

Ascoli  and  Izar,  lowering  of  surface  tension  of 
s3rphiUtic  sera,  78. 

Asphyxia,  recurrent  local,  of  fingers,  in  reality 
syphilitic  phlebitis,  150. 

Asthma,  symptoms  of,  in  syphilitic  myocarditis 
of  left  ventricle,  149. 

Ataxia,  Friedrich's,  not  of  syphilitic  origin,  271. 

severe,  rare  in  congenital  syphilitic  de- 
generative myelitis,  271. 

Ataxy,  locomotor,  term  replaced  by  that  of 
degenerative  myelitis,  244. 

Atoxyl,  281. 

action  judged  by  clinical  methods,  282. 

formula  of,  281. 

superseded  by  arsacetin,  281. 

— —  toxic  action  of,  281. 

instability  of,  281. 

See  also  AmUyojna  (Atoxyl). 

Auditory  nerve  lesions  after  salvarsan,  309. 
Azo-dyes,  value  for  method  in  vivo  not  satis- 
factory, 27. 

Bacilli,  morphology  of  little  help  in  differentia- 
tion of,  60. 

Bacillus  (Duorey's),  11,  254. 

— — •  pus-producmg  organism,  133. 

Bacillus  coli  communis,  endotoxine  of,  299. 

Bacteria  multiplication  in  syphilitic  bodies, 
precaution  against,  45. 

Baermann.     See  Klingmiiller  and  Baermann. 

Balanitis,  differential  diagnosis  of,  467. 

simple,  causes  of,  464. 

treatment  of,  407. 

Balanitis  erosiva  et  gangraenosa,  461,  466. 

— — •  diagnosis  of  primary  chancre  from,  134. 

Balanitis  erosiva  circinata,  465. 

Balanitis  gangrenosa,  465. 

Balfour,  "  infective  granule  "  of  Spirochaetae, 

4. 
Ballenger's  "sealing  in"  method  in  gonorrhoea,' 

384. 
Balsamic  nephritis,  382,  404. 
Banti's  disease,  syphilis  sometimes  cause  of,  180. 
Barensprung   congenital  syphilitic   disease   of 

suprarenals,  270. 
Barium  sulphate,  action  by  precipitation,  78. 

effect  on  sera  treated  with,  78. 

modification,  Wechsclmann's,  77. 

non-colloidal,  77. 

positive  reaction  from,    how   increased. 


77. 


2  r  2 


594 


INDEX. 


Barium-sulphate  raises  amino-acid  content  of 

syphilitic  sera,  91. 
Barker's  lumbar  puncture  needles,  182. 
Bartholinitis,  gonococcal,  428,  430,  434. 
Baths  in  treatment,  353. 
Bayliss,  phenomenon  of  adsorption,  25. 
Benzene,  empirical  formula  of,  270. 
Berlin  blue,  substances  staining,  35,  36. 
Berlin  blue  formation,  nature  of,  37. 

reaction,  amino-acids  giving,  38. 

given     by     pseudo-chylous     fluid     with 

dextrose,  49. 

Bier's  treatment  in  arthritis,  411. 

Bile-ducts,  syphilitic  catarrh  of,  associated  with 
catarrh  of  duodenum,  176. 

Bilharzia,  treatment  of,  349. 

Bisgaard,  increase  of  total  nitrogen  in  cerebro- 
spinal fluid  during  death  agony,  85. 

• total  nitrogen  in  normal  cerebro-spinal 

fluid,  192. 

Bladder,  gonococcal  infection  of,  397. 

gummatous  ulceration  of,  154. 

syphilis  of,  153,  154. 

weakness  in  syphilitic  meningo- myelitis, 

242. 
Blastomycosis,  diagnosis,  143. 
Blephoroplasts,  definition  of,  10. 
Blindness  following  use  of  salvarsan,  483. 

not  caused  by  salvarsan,  157. 

Blondes,  greater  prevaleiace  of  Leucoderma  colli 

in,  256. 
Blood,  alkalinity  of,  278. 

basophile,  582. 

changes  in  syphilis,  150,  151. 

circulating,  source  of  lymphocytes  reach- 
ing, 151. 

— - — •  formation  by  liver,  capacity  retained  in 
congenital  sjrphilis,  274. 

in  cerebro-spinal  fluid,  origin  of,  184. 

method    of    obtaining   from    infant    for 

doing  Wassermann  reaction,  103. 

positive    Wassermann    reaction    in,    in 

degenerative     myelitis     and     encephalitis, 
218. 

protective    substances    against    syphilis 

circulating  in,  218. 

— — •  rcagin  in  cerebro-spinal  fluid  invading, 

193,  194. 
Blood-cells  in  cerebro-spinal  fluid,  185. 

•  method  of  counting,  185. 

nature  of,  185. 

origm  of,  186,  187. 

• — ■ ■ —  staining  method,  185. 

Blood  corpuscles,  red,  changes  in  only  occur  in 

syphilitic  anaemia,  150. 
forms  of,  how  distinguished  from  female 

gametes,  22. 

function  of,  286. 

— — -    See  also  Sheep's  red  blood  corpuscles. 


Blood  corpuscles  red,  supply,  effect  on  S3rphilitic 
osteo-periostitis  of  long  bones,  171. 

Blood-vessels,  as  path  of  invasion  of  meninges 
by  syphiUtic  organisms,  210. 

gonococcal  infection  of,  413. 

lesions  of,  why  common  in  syphilis,  123. 

local,  inflammation  of,  due  to  spores,  123. 

of  spinal  cord,  210. 

syphilitic     inflammatory     changes     in, 

207. 

Body,  systemic  and  nervous  portions  indepen- 
dent, 217,  218. 

Body  fluids,  precise  chemical  composition  un- 
known, 278. 

Bone-marrow,  13'mphocytes  formed  in,  537. 

source  of  lymphocytes  reaching  circula- 
tion, 151. 

Bones,  congenital  syphilitic  diseases  of,  264. 

gonorrhoea  of,  412. 

• •  gumma  of,  266. 

sjrphiUtic  rarefaction  of,  266. 

Bones  and  jomts,  syphilitic  diseases  of,  169. 
aggravated  by  mercury  in  excess, 

169. 
irritation  and  trauma  in  relation  to, 

172. 
Borax  methylene  blue,  addition  of  dextrose  to, 

28. 

method,    for    demonstration    of    living 

Spirochaeta  pallida,  62,  63. 

value  for   staining   syphilitic   bodies   in 

vivo,  28. 

Bordet  and  Gengou,  complement  fixation  test 
of,  71. 

demonstration  of  antibody  by  com- 
plement fixation  test,  69. 

Bradycardia,  pathognomonic  of  syphilitic  car- 
diac lesion,  149. 

-  physiological,  extreme  rarity,  149. 

Bra.in,  defective  development  of,  in  congenital 
syphilis,  271. 

-  degenerative  lesions  of,  congenital  syphi- 
litic, late  appearance  of,  271. 

-  gumma  of,  230,  330. 

-  situation  of  phases  of  leucocytozoon  in,  21U. 
212. 

Spirochaeta  pallida  in,  210. 

syphilis  of,  cases  diagnosed  as,  214. 

syphilitic   degenerative  lesions  occur  in 

any  part  of,  217. 

diseases    of,    content    of    cerebro- 

spuial  fluid  in,  194. 

lesions  of,  ameningeal,  239. 

■ meningeal,  237. 

onset  explained  on  hyper- 
sensitiveness  theory,  230. 

Brain  pressure,  prevention  by  injection  of 
adrenalin,  184. 

relief  of  by  lumbar  puncture,  184. 


INDEX. 


595 


Brain    pressure    and   spinal    cord,    syphilitic 

lepto-meningitis  of,  207,  208. 
Broncliiectasis,    special    feature    of    syphilitic 

disease  of  lungs,  168. 
Bronchitis,  syphilitic  chronic,  ulcerative,  166. 

diagnosis  difficult,  106. 

method  of  termination,  166. 

Bruck.     See  Wassermann  and  Bruck. 
Bubo,  followuig  soft  sore,  358,  366. 

treatment  of,  369. 

Bursae,  sj'phiUtic  lesions  of,  173. 
Bursites,  gonococcal,  406. 

Button  chancre  in  skin  of  penis,  129. 
Calcareous  plates,  absence  in  syphilitic  aortitis, 

148. 
Calcium  chloride,  solution  of,  action  on  nuclei 

of   syphilitic    bodies   and   on   herring's   roe 

compared,  43. 
■ content,      diminished       in       syphilitic 

aortae,  148. 

salts,    deficiency    in    syphilitic     aortae 

shown  by  ash  analyses,  85. 

in  syphilitic  sera,  amount  of,  87. 

Cancer,  cause  of,  508. 

schools  of  thought  on,  504. 

following    but    not    caused    by     leuco- 

plalda,  163. 

inflammatory   changes  in,  produced   by 

syphilis,  turning  to,  164. 

parasites  of,  so-called,  description  of,  506. 

Carbohydrates,  not  found  in  svphilitic  bodies, 

48. 
Carbol-pyronin-methyl     green,     as    stain   for 

syphilitic  organisms,  33. 
Carcinoma.     See  Cancer. 
Catalysts,  arsenic  and  mercury  as,  290. 
Cavernitis  gonorrhoica ,  389. 
Cell,  developed  from  lymphocytes,  529. 
Cells,  aminoplasma  stainmg  of,  502. 

differentiation  of,  530. 

division  and  multiplication  of,  589. 

— —  epithelial,  destructive  to  gonococcus,  374. 

r'lle  in  inflammation,  501. 

living  and  dead,   difference  in  staining 

capacities  of,  26. 

plasma,  hyaline  masses  of,  502. 

. pseudo-parasitic  division  by  amitosis  and 

mitosis,  507. 

role  of  in  inflammation,  580. 

Cerebrin,  action  oii  complement,  80. 
Cerebro-spinal  fluid  albumin  in,  187,  189. 

—  excess  of  before  treatment,  205. 

— —  blood  in,  184. 

blood-cells  in,  185. 

— — •  cases  of  early  generalised  sj'philis  showing 
pathological  clianges  in,  201. 

change    from   normal    to    pathological, 

205. 

• effect  of  salvarsan  on,  205,  206,  207. 


Cerebro-spinal  fluid,  examination  of,  182. 

globulin  in,  187. 

increase  of  Wassermann  reaction  in  just 

before  death,  192. 

in  degenerative  myelitis,  245. 

in  syphihtic  cerebral  disease,  increase  of 

lipoids  in,  192. 
■ total  nitrogen  content,  192. 

increase  of  total  nitrogen  in  during  death 

agony,  85. 

lymphocytosis  of,  205. 

normal,    in    cases    of    Argyll-Robertson 

pupils,  186. 
total  nitrogen  in,  192. 

oxydase  reaction,  192. 

persistence  of  Wassermann  reaction  in, 

196. 

protective  capacity,  effect  of  antibodies 

on,  221. 

protective  substances  against  syphilis  in, 

218. 

protein  in,  187. 

excess  of,   191. 

influence  of  treatment  on,  192. 

rcagtn  in,  invading  blood,  193,  194. 

origin,  78. 

source  of,  193. 

testing  of,  328. 

total  nitrogen  relation  to  Wassermann 

reaction,  192,  193. 

Wassermaim  reaction  in,  193. 

in  degenerative  myeUtis,  196. 

withdrawal  of,  182,  183. 

• for  testing  purposes,  183. 

headache  following,  183. 

injection  of  saline  after,  183. 

needle  for,  182. 

• to  relieve  pressure,  183. 

Cervicitis,  gonococcal,  430. 
Cervix  uteri,  chancre  of,  253. 

differential  diagnosis,  253,  254. 

— ■ —  instrumentation  to  be  avoided,  433. 
Chancre-like  sore,  preccdmg  and  not  preceding 

recurrent  generalised  rash,  141. 
Chancre  redux,  14. 
Chancres,  clinical  features,  diversity  in,  11. 

development  of,  119. 

female,  echthymatous,  252. 

erosive,  252. 

— furrowed,  253. 

■ hypertrophic,  252. 

• ■  lenticular,  252. 

■ mixed,  infection  with  soft  sore,  253. 

• papulo-pustular,  252. 

primary,  251. 

. pseudo-membranous,   252. 

ulcerative,  252. 

genital  and  extragenital,  ratio  between, 

124. 


596 


INDEX4 


Chancres,  human  ulcerative,  with  extra-cellular 
development  of  spLrochaetae,  121. 

hypertrophic,  162. 

simulating  large   spored  ringworm 

lesion,  162. 

induration  of,  119. 

intra-urethral,  area  of  induration,  127. 

phagcdacnic,  effect  on  nearest  lymphatic 

glands,  122. 

primary,  124,  128. 

■ —  aberrant    development    of    Lexico- 

cytozoon  syphilidis  in,  127. 

• becoming  infected  or  phagedaenic, 

120. 

contiguous  on  penis,  129. 

■ date  of  appearance  after  connection, 

125. 

development  of,  119,  133. 

diagnosis,  133. 

by  bacteriological  examina- 
tion, 125. 

from  aphthous  ulcer,  134. 

from  Balanitis  erosiva  et  gan- 
grenosa, 134. 

■ from  Herpes  geniialis,  134. 

from  soft  sore,  133. 

from  traumatic  lesion,  133. 

only  certain  method  of,  126. 

pomts  in,  124. 

digital,  132. 

ecthymatous,  130. 

• erosive,   128. 

•  Spirocliaeta  pallidaTaoateas'iiy 

obtained  from,  129. 

extra  genital,  124,  132. 

diagnosis  from  pyogenic  infec- 
tion, 132. 

form  not  followed  by  further  symp- 
toms, 14. 

formed  by  asexual  development  of 

Leucocytozoon  syphilidis,  120. 

■ genital,   124. 

histological      and      bacteriological 

study,  a  guide  to  prognosis,  129. 

human  and  experimental,  difference 

between,  120. 

■ hypertrophic,  131. 

in  corona,  with  phimosis,  131. 

implication    of    lymphatic    glands, 

greatest  m  neighbourhood  of,  144. 

— indication  for  removal,  120,  125. 

situation  where  most  marked, 

127. 

intra-urethral,  131. 

lvmi>hadenitis  accompanying, 

131. 

loss    of    surface    corresponds   with 

celMar  infiltration  in  corium,  127. 

nature  of,  120. 


Chancres,  primary,  necrosis  of,  126,  128. 

of  experimental  syphilis,  tendency 

to  ulceration,  120. 

— ■ of  tonsil,  164. 

■ diagnosis  from  Vincent's  an- 
gina, 164,  165. 

papulo-erosive    and    papulo-ulcera 

tive  course  of  syphilis  after,  compared,  130. 
worst   cases  of  syphilis  arise 

from,  129. 

papulo-tJcerative,  129. 

simple,  130. 

removal     of    crust    of    ulcer 

before  diagnosis,  130. 

phagedaenic,  126,  131. 

— —  pseudo-membranous.  131. 

■ secondary  infection,  126. 

site  of  breaking  down  under  trauma, 

13. 

ulcerative  stages,  126,  128. 

variation  in,  11. 

See  also  Button  chancre. 

Chemoceptor,  definition  of  term,  283. 
Ghemotherapj',  results,  how  obtained,  285. 
— ■ —  Ehrlich's  conception  of,  283. 

Child,  syphilitic,  danger  of  producing,  261. 
negative  Wassermann  reaction  in, 

becoming  positive,  257. 
treatment     advisable     in     parents 

after  birth  of,  257. 
Child-bearing    period,    positive    Wassermann 

reaction  in  women  indication  for  treatment 

throughout,  256. 
Children,  healthy,  of  sj-philitic  parents,  261. 

non-sj'philitic,  births  of,  intervening  be- 
tween those  of  syphilitic,  260. 

sj^hilitic,  early  death  of,  260. 

Chloride    content    of    syphiUtic    and    normal 

lymphatic  glands,  method  of  estimation,  87. 
Chlorine,  monovalent  element,  276. 
Chloro-lymphadenosis,  541. 
Chloromata,  541. 
Cholangitis,  sj'philitic,  177. 

complicated  by  jaundice,  177. 

Cholesterol,  addition  to  antigen,  73,  74. 

appearance  in  syphilitic  parasites,  49. 

Choroid  plexuses,  epithelial  cells  of,  constitu 

tion,  78. 

derivation  of  reagin  from,  78. 

Choroiditis,  congenital  syphihtic,  273. 

syphilitic,  155,  156. 

retinitis  associated  ■with,  156. 

Chromatin,  specific  action  of  methyl  green  for, 

30. 
Ciliary  body,  gumma  of,  rare,  155. 
Circumcision,  reasons  for  performing,  461,  464, 

470. 
Citron's  method  of  preparing  neutral  emulsion, 

338. 


INDEX. 


597 


Clavicles,  osteoperiostitis  of,  172. 

Clove  oil,  not  to  be  used  as  clearing  fluid   in 

staining  syphilitic  organisms,  33. 
Cocci  accompanying  svphilitic  parasites,  result, 

145. 
Coccidiosis  avenf.rea,  case  of,  18. 

inclusion  bodies  in,  20. 

treatment,  19. 

histological  examination  of  early  papule, 

19. 

Coitus  inlerruptus,  480. 

urethritis  due  to,  417. 

Cold,  formation  of  reagin  increased  !>y,  89. 
Cold  applications  in  epididymitis,  402. 
Colles's  law,  explanation,  250. 

• validity  of,  251. 

Colloid,  use  of  term,  501. 
Colloidal  particle  increase  of  in  antigen,  72. 
Colloidal  particles  larger  in  syphilitic  than  in 
normal  sera,  84. 

of  dyes,  positively  and  negatively  charged, 

25. 

Colloidal  solutions,  decrease  of  surface  tension, 

how  produced,  96. 
Colloidal   and   non-colloidal   bodies,   efEect   on 

serum  reactions  compared,  77. 
Colour  test  in  diagnosis  of  syphilis,  69. 
Colpitis  in  women,  428. 
Complement,  adsorption  bv  reagin  explained, 

95. 
■ action  of,  destroyed  bv  deep  anaesthesia, 

65,  80. 

how  increased,  81. 

• pure  lecithin  globulin  on,  79. 

best  obtained  from  guinea  pig,  65. 

cellular  origin,  84. 

destruction  of.  following  by  disappearance 

of  oxydase  reactions,  83. 

does  not  keep  when  diluted,  74. 

fixation  of,  haemolysis  in  test  tubes  in 

relation  to,  67,  68. 

fixation  test  in  gonorrhoea,  435,  442. 

identical  with  antibody,  S3. 

with  lipoid-globulin,  83. 

lipoid-globulin  particles  in  normal  serum 

probably  consist  of,  82. 

method  of  preservation,  80. 

most  important  factor  in  Wassermann 

reaction,  98. 

once  destroyed  cannot  be  renewed,  81. 

precipitation     in     dialysmg     apparatus, 

result,  96. 

rapid  disappearance  when  kept,  80. 

• relation  to  oxydases,  82,  83. 

standardised  strength  must  be  employed, 

98. 
strength     of,     method     of    ascertaining, 

66. 

substances  destroying,  81. 


Complement,  syphilitic  serum  giving  positive 
nin-hydrin  reaction  in  presence  of,  96. 

thcrmolability  of,  80,  81. 

Complement  and  antibody,  chemically  identical, 

76. 

identity  of,  82. 

— —  fixation  by  Spirochaeta  pallida  in  presence 

of  antibody,  61. 
in  Wassermann  reaction,  essentials  for,  73. 

fixation  test,  71. 

■ demonstration  of  antibody  by,  69. 

use  of  active  sera  in  connection  with,  76. 

molecules  and  reagin  homologous,  90. 

precipitation  of,  70. 

Condyloma  acuniinaium,  467. 
Condyloma  latum,  137. 
Condylomata,  congenital  syphilitic,  263. 
Condylomata  lata  around  anus,  176. 

following  use  of  salvarsan,  302. 

Congenital  syphilis,  treatment  of,  326. 

Congo  red,  adsorption  of,  in  different  concen- 
trations, 26. 

Conjunctivitis,  gonococcal,  in  adults,  420. 

in  new-boni,  422. 

Coimective-tissue  cell,  588. 

• • function  of,  529. 

in   which   asexual  spore   cysts  develop, 

how  affected,  56. 

invasion  in  development  of  asexual  stage 

of  Leucocytozoon  syphilidis,  127. 

proliferation  of,  127. 

Constipation  in  sexual  neurasthenia,  478,  481. 
Corium,  cellular  infiltration  in,  loss  of  surface 
of  syphilitic  sore  corresponds  with,  127. 

degeneration   of,   Icad.s   to   formation   of 

pustule,  136. 

Corona,  induration  most  marked  when  chancre 

situated  in,  127. 
Cowperitis  gonorrhoica,  388. 
Crystalline  forms  of  plasma  cell,  533. 
Cutireaction  in  diagnosis  of  syphilis,  113. 
• rationale  of,  115,  116. 

sypliilitic,  positive,  116,  117. 

• simulating  syphilitic  lesions,  110. 

Cycling,  urethritis  set  up  by,  416. 
Cystitis,  gonorrhoea!,  377. 

gonorrhoica,  397. 

■ syphilitic,  154. 

Cytorrhycles  hds,  1. 
Dacryo-cystitis,  syphilitic,  155. 
Dactylitis  syphilitica,  266. 
Deaf-mutism,  congenital  syphilitic,  273. 
Deafness,  following  salvarsan,  309. 

syphilitic,  158. 

due  to  neuritis  of  auditory  nerve, 

159. 

of  cranial  nerves,  160. 

• early,  158. 

effect  of  treatment  on,  160. 


INDEX. 


Deafness,  syphilitic,  in  early  syphilis,  158. 

late,  161. 

Death,    enormous    increase    of    Wassermann 

reaction  in  cerebro-spinal  fluid  just  before, 

192. 

Wassermann  reaction  positive  in  blood 

taken  just  before  or  after  in  non-syphilitic 
cases,  85,  86. 

Death   agony,   increase   of   total  nitrogen   in 

cerebro-spinal  fluid  during,  85. 
Deferentitis  gonorrhoica,  400. 
Dejliivium    capillilii,    in    congenital    syphilis, 

264. 
Degeneration,  products  of  protein  metabolism, 

530. 
Dermatitis,  seborrhoeic,  mistaken  for  syphilitic 

rash,  263. 
Development,  errors  of,  in  relation  to  syphilis, 

261 
Dextrose,  addition  to  borax  methylene  blue,  28. 
presumably  absent  in  syphilitic  bodies, 

49. 

pseudo-chylous  fluid  with,  reaction  ob- 
tained under,  49. 

Diabetes  insipidus,  aberrant  form  of  syphilis 
associated  with,  15. 

association  with  congenital  sj'philis,  17. 

■ lesion   in   pituitary   body   in   congenital 

sj^hilis,  272. 

Diagnosis,  differential,  Wassermann  reaction  in, 
104. 

Dialysing  apparatus,  precipitation  of  comple- 
ment in,  result,  96. 

Diday's  irrigation  in  gonorrhoea,  383. 

Digestive  system,  disorders  following  salvarsan, 
300. 

Digestive  tract,  congenital  syphilitic  disease  of, 
268. 

Diploii,  gummatous  osteomyelitis  of,  171. 

Diplopia,  complicating  syphilitic  cerebro-spinal 
meningitis,  234,  236. 

Distillation,  methods  of,  297. 

Doelfle,  supposed  pathogenic  agent  of  syphilis,  1. 

Drugs  in  treatment  of  gonorrhoea,  383. 

used  in  treatment,  methods  of  adminis- 
tering them,  337. 

Dubois's  abscesses  of  th3Tiius,  270. 

Ducrey'a  bacillus,  11,  358. 

types  of,  366. 

Duodenum,    syphilitic   catarrh   of,   associated 

with  catarrh  of  bile  ducts,  176. 
Dupuytren's  contraction  and  Induraiio  penis 

plaslica,  474. 
Dydynski.     See  Halhau  and  Dydynski. 
Dyes,  acid,  fixed  protoplasm  stains  best  with, 

"31. 
•  taken  up  by  dead  cells,  26. 

basic,    destruction    of    affinity    of    Nissl 

bodies  of  nerve  cells  for,  26. 


Dyes,  acid,  taken  up  by  living  cells,  26. 
value  for  in  vivo  method,  29. 

colloidal,  nature  of,  25. 

electro-negative      and      electro-positive, 

several   effects   of   kations   and   anions   on 
adsorptive  powers,  26. 

fixation  of,  accelerated  by  heat,  26. 

giving  best  results  for  staining  in  vivo, 

27. 

positively  and  negatively  charged  col- 
loidal particles  of,  25. 

sensitive    to    electrolytes    in    adsorptive 

capacity,  26. 

Ear,  internal,  congenital  sj-philitie  inflam- 
mation of,  273. 

Ehrlich,  conception  of  chemotherapy,  283. 

steps  leading  to  discovery  of  salvarsan 

by,  284. 

theories  of,  347. 

toxic  action  of  oxidation  product  of  sal- 
varsan, 224,  225. 

Ejaculatio  praecox,  480. 

Elastin,  530 

Electrolytes,  extraction  from  cells  of  syphihtic 
bodies,  41,  42. 

importance  of,  in  staining  processes,  26. 

presence  of  factor  in  preparation  of  histo- 
logical specimens,  26. 

sensitiveness  of  dyes  to,  in  adsorptive 

capacity,  26. 

Electrolytic  theory  in  staining  of  syphihtic 
organisms,  31. 

Elephantiasis  following  gumma,  146. 

■ syphilis  as  cause  of,  145,  146. 

Embryonic  areas,  appearance  in  organs  in  con- 
genital syphilis,  274. 

Emissions,  nocturnal,  478. 

Emulsion,  neutral,  preparation  of,  338 

Encephalitis,  congenital  syphilitic  degenerative, 
271.272. 

degenerative,  ameningeal  form  of,  317. 

of  insane,  lipoid  cell  degeneration  in, 

85. 

onset  explained,  230. 

result  of  luetin  reaction  in,  114. 

Wassermann  reaction  in,  104. 

degenerative     syphilitic,     albumin     and 

globulin  content  in,  cerebro-spinal  fluid  in, 
189. 

content  of  cerebro-spinal  fluid  in, 

194,  195. 

diagnosis     by     Kaplan's     goldsol 

curves,  196-198. 

from     meningeal     lesion     by 

blood-cell  counts  in  cerebro-.spinal  fluid,  186. 

Wassermann  reaction  in  cerebro- 
spinal fluid  in,  196. 

haemorrhagic,  222. 

following  salvarsan,  223. 


INDEX. 


599 


Encephalitis,  haemorrhagic,  occurring  inde- 
pendently of  salvarsan,  223,  224,  228. 

occurring  seven  years  after  infec- 
tion, 227. 

syphilitic,  184. 

treatment,  184. 

huemorrhagica,  hopeless  case,  how  saved, 

226. 

Syphilitic,    not    preceded    by    vascular 

lesions  of  nervous  system,  213. 

degenerative,  240. 

• anti-syphilitic  treatment  un- 
satisfactory, 241. 

• cause  of  death  in,  212. 

•  cerebral  cortex  analogous  to 

degenerative  myelitis  of  posterior  cord, 
217. 

• development  of  spirochaetae  pro- 
nounced in,  212. 

• incurability,  212. 

inflammation  of  pia  arachnoid 

in,  210. 

■ meningeal,    prognosis    better 

than  in  ameningeal  form,  240. 

path  of  infection  in,  210. 

positive  Wassermann  reaction 

in  blood  in  cases  of,  218. 

preceded  by  vascular  lesions 

of  nervous  system,  213. 

pupil  anomalies  less  frequent 

in,  241. 

• site  of  morbid  changes  in,  210. 

non-degenerative,  214. 

• with  late  symptoms,  treat- 
ment, 214. 

treatment  of,  331,  333. 

Endarteritis,  sj^hilitic,  239. 

obliterative,  how  set  up,  123. 

Endocarditis,  gonococcal,  414. 

Endometritis,  gonococcal,  431. 

Endoscopic  examination  of  urethra,  379. 

Endothelial  cell,  role  of,  in  mflammation,  563. 

Endothelial  cells,  527. 

condition  in  case  of  aberrant  form   of 

syphilis,  15,  16. 

containing    circular    masses,    distinction 

from  connective-tissue  syphilitic  bodies,  22. 

in     cerebro-spinal     fluid     in     sypliilific 

meningeal  lesions,  186. 
in  which  asexual  spore  cysts  develop,  how 

affected,  56. 
invasion  in  development  of  asexual  stage 

of  Leiicoq/tozoon  syphilidis,  127. 
Endothelioma,  inflammatory,  563. 
Endotheliomata,  malignant  and  intermediate, 

578. 

new  growth,  565. 

pigmented  and  non-pigmented,  566. 

Endotoxines,  bacterial  action  of,  299. 


Endotoxines,  bacteri:il  action  of,  toxicity  oi 
salvarsan  increased  by,  299. 

Encsol  preparation,  351. 

Enzyme  action,  acceleration  of,  286. 

Enzymes,  oxidising  action  of,  how  increased, 
286. 

Eosinophilc  cell,  286. 

Eosinophile  counts  in  sj-philis,  1.50,  151. 

Eosinophilc  granules,  nature  and  function,  286. 

Epididymitis,  syphilitic,  diagnosis  from  tuber- 
cular, 154. 

early,  154. 

vaccine  treatment  of,  403. 

Epididi/mitis  gonorrhoica,  401,  453. 

Epilepsv,  association  with  congenital  S3rphilis, 
272.  ' 

following  salvarsan,  300. 

Jacksonian,  after  salvarsan,  313. 

Epiphj'ses,  enlargement  of,  before  first  year 
sign  of  congenital  syphilis,  274. 

separation   of,   in   Osleochondrilis  syphi- 

Ulica,  265. 

• — ■ —  pathological  changes  resulting  in, 

265. 
Epithelioma,  malignant,  500,  538. 

prickle-celled,  510. 

malignant,  500. 

squamous-celled,  510. 

Epithelioma  adenoides  ci/slicnm,  511,  514. 
EpitheUomata,  cutaneous,  classification  of,  509, 

512. 

mUia  present  in,  515. 

Erythema     induratum     differentiation     from 

gumma,  143. 
Erythema  following  salvarsan,  224. 
Erythema  mvltiforme  caused  by  syphilis,  142. 
Erythema  nodosum,  425. 

caused  by  syphilis,  142. 

■ syphililicnm,  147. 

Ervthemata,  congenital  syphilitic,  nature  of, 
262. 

• toxic  after  salvarsan,  301. 

Eugenic  Committee,  aims  of,  495. 

Eyes,  congenital  syi^hilitic  diseases  of,  273. 

gonorrhoeal  diseases  of,  420,  423. 

syphilis  of,  155. 

Fallopian  tubes,  gonococcal  infection  of,  431.    • 

Father  and  mother,  syphilis  in,  relative  im- 
portance, 250. 

Fathers,  prospective,  subjects  of  syphUis,  drastic 
treatment  necessary  in,  256. 

Fatty  acid  emulsions  in  sera  exhibit  strong 
anti-complementary  action,  90. 

mixtures,  action  on  complement,  79. 

Fatty  acids,  302. 

increase  amino-acid  content  of  syphilitic 

sera,  90. 
unsaturated,   contained   in   envelope   of 

Spirochaeta  pallida,  61 


600 


INDEX. 


Females,  congenital  syphilitic  iritis  conimoner 

in,  273. 
Females    and    males,    lymphocyte    count    in 

S3rphilis  compared,  151. 
Ferments,  lipoids  carriers  of,  286. 

oxydase,  287. 

Ferricyanide,  ferric,  action  of  amuio-acids  on, 

37. 
staining  of  sections  of  syphilitic  bodies 

with,  35. 
Fertilisation,  chemistry  of,  17,  18. 

increase  of  acid  in  female  cell  during,  17. 

influence  of  salts  on  process  of,  18. 

processes  of,  requirements,  17. 

Fever,  intermittent  in  syphilitic   cirrhosis    of 

liver,  178. 
Fildes.     See  Mackintosh  and  FUdes. 
Filter-passer,  syphiUtio  virus  not  a,  1. 
Finger,    chancre    of.     See    Chancre,    primary 

digital. 
Fingers,  recurrent  local  asphyxia  of,  in  reality 

syphilitic  phlebitis,  150. 
Fischer's  theory  of  structure  of  protein,  88. 
Fixing  reagents,  employed  in  staining  syphilitic 

organisms,  31,  32. 
Foetus,     macerated    sj'philitic,     abortion    of, 

260. 
Folliculilis  gonorrhoica,  389. 
Foreskin,  long,  balanitis  with,  464. 

tight,  effects  of,  467. 

Formalin,  as  fixing  reagent  in  staining  of 
syphihtic  organisms,  32. 

cauterisation  with,  433. 

effect  on  antigenic  action,  72. 

in  sera  exhibits  strong  anti-complemen- 
tary action,  91. 

diminishes  amino-acid  content  of  syphi- 
litic sera,  91. 

Fornet  and  Schereschewsky,  precipitation  test, 
69. 

Fracture,  spontaneous,  following  syphilitic 
osteomyelitis,  172. 

Freezing  pomt  of  syphilitic  sera,  75. 

• •  compared  with  that  of  normal  sera, 

75. 

French  arsenical  compounds,  282,  283. 

Fuohs-Rosenthal  method  of  countmg  blood- 
cells,  185. 

Furunculosis,  following  salvarsan  injections, 
301. 

Galaotosuria,  alimentary  in  syphilitic  hepatitis, 
178. 

Galyl,  282. 

constitutional  formula,  283. 

phosphorus  in,  283. 

-  treatment  with,  347. 
Gamete,  definition  of,  10. 

—  female,  fertilisation  by  Spirochaeta  pallida, 
9.  10. 


Gametes,  female,  and  forms  of  red  blood  cor- 
puscle, distmction  between,  22. 
Gametocytes,  definition  of,  10. 

female,  circular  bodies  in  mflamcd  tissue, 

resembling,  21. 

staining  during  impregnation,  58. 

male,    richer   in   lecithin   globulin   than 

female,  57. 

male  and  female,  development,  56. 

of  Leucocytozoon  syphilidis,  9. 

Gangrene  of  penis,  466. 

Gastric  crises  in  degenerative  myelitis,  176,  246. 
Generative  organs,  female,  syphilis  of,  255. 

granuloma  of,  470,  499. 

Gengou.     See  Bordet  and  Gengou. 
Genito-urmary  tract,  male,  syphilis  of,  152. 
Giemsa's  stain,  418. 
Glans  penis.  Lichen  planus  affecting,  143. 

■  sores  on  frequently  non-indurated,  127. 

Globulin,  formation  of  pigment  from,  507. 

importance  to  life,  52. 

in  cerebro-spinal  fluid,  187. 

decrease  of,  with  negative  Wasser- 

mann  reaction,  191. 
existing  in  form  of  lipoid-globulin, 

191. 
in   degenerative   syphilitic   lesions, 

reason  for  greater  amount,  191. 

reducing  action,  191. 

tests  for  detection,  187,  188. 

•  pure,  isoelectric,  86. 

See  also  Albumin  and  globulin. 

Globulm  complexes,  503. 

•  increased  in  syphilitic  sera,  92. 

— ■ —  pyroninophile  protein  of  syphilitic  bodies 

a,  41. 
Globulin  excretion  in  urine,  effect  of  mercury 

upon,  152. 
lipoid  complexes,  503. 

tost,  failure  after  injection  of  serum,  347. 

Globulinuria    in    progressive    late     syphilitic 

nephritis,  153. 

— — -  in  late  syphilis,  153. 

Glucosamine,  absent  in  syphilitic  bodies,  48. 

Glycosuria,  intermittent  in  syphilitic  pan- 
creatitis, 179. 

Gold  suspension,  colloidal,  preparation  of,  188. 

Goldsol  curves,  Kaplan's,  in  diagnosis  of  de- 
generative encephalitis  from  degenerative 
myelitis,  196-198. 

■ of    early    syphilitic    infection    of 

nervous  system,  205,  206. 

Goldsol  indicator,  188. 

. reaction,  80. 

Lange's  method  for  testing  presence  of 

globulin  in  cerebro-spinal  fluid,  188. 

Gonargin,  442,  452. 

Gonococcal  emulsions  in  complement  fixation 
test,  442. 


INDEX. 


601 


Gonococcal  warts,  467. 

Gionococcus,  antigens  from  different  strains  of, 
439. 

epithelial  cells  destructive  to,  174. 

Gram's  mctliod  of  staining,  371. 

fixation  of  complement,  440. 

incubation  peroid,  373. 

methods  of  destruction  of,  382. 

■  Pappenheim's  method  of  staining,  372. 

spread,  of  the  organisms, 

staining  metliods  contrasted,  371. 

•  V.  Leszcznysky's  method  of  staining,  372. 

Gonorrlioea,  371. 

acute,  378. 

■  and  marriage,  490. 

antiseptic  applications  in,  383. 

argyrol  in  treatment  of,  384. 

• — — •  artliritis  complicating,  407,  454. 

Arthritis  deformans  following,  173. 

Ballenger's  "sealing  in"  method,  384. 

bursitis  complicating,  406. 

cardiac,  413. 

cavernitis  complicating,  389. 

chronic,  378,  380. 

complement  fixation  test,  435. 

complications  of,  388. 

due  to  spread  b}'  metastasis,  406. 

— —  conjimctivitis  complicating,  420,  422. 

Cowperitis  complicating,  388. 

cystitis  complicating,  397. 

— ■ — •  deferentitis  cora])licating,  400. 

endocarditis  complicatmg,  414. 

epididymitis  complicating,  401,  4.53. 

•  folliculitis  complicating,  389. 

hegonon  in  treatment  of,  384. 

•  Herpes  genitalis  following,  478. 

in  women,  427,  430. 

manner  of  spread  of  the  organisms,  373. 

•  metritis  and  metrorrhagia  following,  255. 

muscidar,  412. 

nervous  system  involved,  413. 

——  ocular,  42*0,  423. 

osseous,  412. 

paraurethritis  complicating,  391. 

■ — —  pelvic,  432. 

perifolliculitis  complicating,  389. 

proctitis  complicating,  404. 

prophylaxis  of,  382. 

— - —  prostatitis  complicating,  391. 

protargol  in  treatment  of,  384. 

pyelitis  complicating,  403. 

pyelonephritis  complicating,  403. 

• — ■ —  rashes  in,  424. 

secondary  infection  in,  380. 

-  symptoms  of,  375,  382. 

tenosynovitis  complicating,  406. 

treatment  of,  abortive,  384. 

drugs  in,  383. 

hygienic,  382. 


Gonorrhoea,  treatment  of,  in  women,  432. 

■  injections  in,  383. 

lavage  in,  385. 

local,  382. 

symptomatic,  382. 

urethral  comj)lications,  390. 

vaccine,  411,  4.50. 

ureteritis  complicating,  403. 

urethritis  in,  37(i,  452. 

— ■ complications,   388. 

urinary  conditions  in,  377. 

vascular,  413. 

vesiculitis  complicating,  399. 

Gonorrhoeal  neurasthenia,  480. 

Gram's  method  of  staining  gonococcus,  371. 
Granoplasm,     beliaviour    of    in    presence    of 
various  acids,  39,  40. 

nature  of,  38. 

Granules,  inject  ive,  4,  5. 

oxydase  reactions  of,  287. 

Oranuloma  inguinale,  15. 

extracellular  bodies  in,  473. 

geographical  distribution,  470. 

intracellular  bodies  in,  473. 

pathology  of,  471. 

protozoal  organism  in,  472. 

Granuloma  pudendi,  470,  471. 
Granuloniata,  499. 

Grey  oil  injections  after  salvarsan,  effect  on 

syphilitic  deafness,  160. 
Group  reactions,  117. 
Group  specificity,  definition  and  explanation, 

285. 
Guanicaine,  352. 
Guinea-pig,  complement  best  obtained  from, 

65. 
Gumma,  cerebral,  230. 

diagnosis  from  female  chancre,  254. 

differentiation    of    Erythema    induratum 

from,  143. 

• — —  elephantiasis  following,  146. 

formation  of,  140. 

following     syphilitic     invasion     of 

artery,  123,  215. 

of  bones,  26fi. 

of  ciliary  body  rare,  155. 

of  heart,  149. 

in  His's  bundle,  149. 

of  iris,  rare,  155. 

of  liver,  congenital  varieties,  209. 

of  testicle,  l.')4. 

of  tonsil,   diagnosis  from  priman,'  sore, 

164,  165. 

Gumma  cerebri,  neo-salvarsan  in,  330. 
Gummata,  congenital,  263. 
in  heart  muscle,  267. 

content  of  cerebro-spinal  fluid  in,  195. 

may  be  of  equal  severity  in  both  sexes, 

257.  258. 


602 


INDEX. 


Gummata,  treatment  of,  330. 
Gummatous  osteomyelitis,  170. 
Gummatous  osteoperiostitis,  170. 
Gummatous  ulceration  of  rectum,  177. 
Guyon's  catheter  in  gonorrhoea,  383. 
Haemangioendotheliomata,      examuiation      of 

nodule,  569. 
microscopical  examination  of  nodule,  571. 

pathology  of,  568. 

Haematogeneous  origin  of  syphilitic  nervous 

lesions,  212,  213,  214. 

Haeraatoxylin,  staining  of  syphilitic  tissues  in, 
51. 

Haemocytometer,  Thoma-Zeiss,  185. 

Haemoglobiuuria  accompanying  tertiary  sy- 
philitic fever,  178. 

spasmodic,     accompanying      Raynaud's 

disease,  149. 

due  to  syphilis,  150. 

Hacmogregarine,  infective  granule  of,  4. 
Haemolysis  in  test  tubes  in  relation  to  fixation 

of  complement,  67,  68. 
Haemolytic   system   and   Abderhalden's   test, 

analogy  between  method  of  action,  95. 
Haemopoetic  system,  sj^j)hilis  of,  144. 
Haemosiderin,  507. 
Hair  foUicules,  510,  522. 
Halbau    and    Dj'dynski,    optic    atrophy    and 

sphincter  (bladder)  paralysis  in  congenital 

degenerative  myelitis,  271. 
Hausmann,     differential     diagnosis     between 

syphilis  and  other  diseases  of  stomach,  175. 
Hazen,  blood  changes  in  sj^hilis,  150,  151. 
Head  and  face,  asymmetry  of,  in  congenital 

syphilis,  271. 
Headache,  causes  of,  in  syphilis,  238. 

following    withdrawal    of    cerebro-spinal 

fluid,  183. 

Heart  diseases,  contraindicating  salvarsan,  313. 

gonococcal  infection  of,  413. 

gumma  of,  149. 

symptoms  in  dcgeneraf  ive  myelitis,  246. 

— ■ —  syphilitic  lesions  of,  148. 

•  early,  diagnosis  difficult,  148. 

late,  148. 

pulse  rate  in,  149. 

Heart-block,   accompanying  gumma  of  His' a 

bundle,  149. 
Heart  muscle,  congenital  gummata  in,  267. 
Heat,  fixation  of  dyes  accelerated  by,  26. 
Heating,  effect  on  syphilitic  sera,  75. 
Heel,  painful,  406. 

Hegonon  in  treatment  of  gonorrhoea,  384. 
Heidenhain,  M.,  specification  of  methyl  green 

for  chromatin,  30. 
HeUer's  test,  187,  205. 
Hemiplegia,  early  syphilitic,  mode  of  onset,  213. 

frequent  early  symptom  of  syphilis,  210. 

syphilitic,  147,  239. 


Hemiplegia,  syphilitic,  early  and  late,  differ- 
ences between,  240. 

transverse   myelitis   analogous   to, 

217. 

Henry,  infective  granule  of  hacmogregarine, 
4,5. 

Hepatitis,  interstitial  sj'philitic,  diffuse,  177. 

• ,  localised,  177,  178. 

interslUialis  et  gummosa,  269. 

syphilitic,  signs  of,  178. 

Herpes  febrilis,  298. 
Herpes  genitalis,  298. 

causes  of,  470. 

causing  sexual  neurasthenia,  478,  481. 

diagnosis  of,  primary  chancre  from,  133. 

• — —  site  of,  469. 

Herpes  iris,  syphilitic,  162. 

zoster,  298. 

Herring's  roe,  action  of  reagents  on,  tested 
against  action  on  nuclei  of  syphilitic  bodies, 
42,  43. 

Herxheimer's  reaction,  303. 

Hip  joints,  both,  Arthrijis  deformans  affecting, 
after  gonorrhoea  and  sj'philis,  173. 

Hirsch's  injection,  352. 

His's  bundle,  gumma  of,  149. 

accompanied  by  heart  block,  149. 

Histidine,  test  for,  46. 

Histone,  503. 

Hochsinger,  congenital  gummata  of  liver,  269. 

• national  loss  by  ante-natal  sypliilis,  250. 

Hodgkin's  disease,  536,  540. 

histology  of,  557. 

Hoffmann,  cause  of  syphilis,  3. 

life-history  of  Spirocliaeta  pallida,  4. 

See  also  MUldens  and  Hoffmann. 

Schaudinn  and  Hoffmann. 

Homy  cysts,  516. 

Hospitals,  special,  abolition  advocated,  497. 

Host,  intermediate,  not  required  by  all  proto- 
zoa, 24. 

Huge's  fluid  for  bathing  of  spiroohaete  films,  63. 

Hutchtuson,  Sir  J.,  congenital  syphihtic  iritis, 
273. 

Hutchinsonian  teeth,  264. 

in    later    life    diagnostic    of   congenital 

syphilis,  274. 

and    nodes    on   tibiae    association   with 

double  interstitial  peratitis,  273. 

Hutchinson's  pill,  354. 

Hyaline  degeneration,  crystal  formation  in,  504. 

masses  of  plasma  cells,  502. 

— ■ —  plasma  cell,  533. 

use  of  term,  501. 

Hydrarthrosis,  chronic  bilateral  due  to  con- 
genital syphilis,  267. 

■ supervening  on  osteochondritis,  266. 

Hydrocephalus  in  congenital  syphilis,  266. 

congenital  syphilitic,  271. 


INDEX. 


6oa 


Hydrocephalus,  congenital,  in  utero,  271. 
Hydrochloric  acid  content,  decrease  in  syphilis 

of  stomach,  175. 
Hydrochloride  of  salvarsan,  formula,  277. 
Hydrolysis   and   precipitation,   Abderhalden's 

test,  process  of,  96. 
Hi/drops  arlicitli,  172,  408,  410. 
Hydroxyl  groups  of  spirochaetae,  305. 

action  of  salvarsan  on,  289. 

Hygiene,   personal,   and  sexual  neurasthenia, 

479. 
"  Hyperideal "  potency  and  toxicity,  294. 
Hypersensitiveness  theory  of  onset  of  cerebral 

syphilis,  230. 
Hypochondria,  sexual,  482. 
"  Ideal  "  potency  and  toxicity,  294. 
Idiocy,   association   with   congenital   syphilis, 

272. 
Incidence  of  syphilis,  statistics  of,  496. 
Indian  ink  method  of  demonstrating  Spirochaeia 

pallida  when  dead,  63. 
Induratio  penis  plastica,  474. 

complications  of,  475. 

Infants,  syphiUfic,  born  without  positive  Was- 
sermann  reaction  in  mother,  250. 

— — -  iiifection  after  birth,  2(30. 

original   method   of   Wasser- 

mann's  reaction,  guide  to,  257. 

■ — •  treatment  during  pregnancies  follow- 
ing birth  of,  essential,  250. 

Infectivity,  variable  syphilitic,  488. 

Inflammation,  reactionary,  303. 

■ less  severe  .with  neo-salvarsan,  319. 

relationship  to  cancer,  508. 

to  mahgnant  disease,  499. 

role  of  cells  in  causation,  580. 

of  endothelial  cell  in,  563. 

•  of  epithelial  cells  in,  501. 

— of  lymphocyte  in,  526. 

of  plasma  cells  in,  534. 

Injections  of  salvarsan  and  neo-salvarsan,  pre- 
paration of,  337,  341,  344. 

of  vaccine,  441,  443. 

Intestines,  congenital  gummatous  ulceration  of, 

268. 

syphilis  of,  176. 

•  commoner   m   congenital   than   in 

acquired  form,  176. 
Intramuscular  injections  of  mercury,  350. 

of  neo-salvarsan,  341. 

of  salvarsan,  337. 

. —  clinical  course  after,  339. 

Intrathecal  injection  of  salvarsanised  serum, 

346. 
Intravenous  injections  of  antimony,  349. 

of  mercury,  349. 

of  neo-salvarsan,  344. 

of  salvarsan,  341. 

of  vaccine,  443. 


Inunction,  mercurial,  352. 

Iodide  rash,  differentiation  from  papulo- 
pustular  sypliilide,  143. 

Iodides  and  mercury,  supplementary  to  sal- 
varsan treatment  of  ssfphilis,  111. 

in  Ulcus  molle  serpiginosum,  365. 

Iodine,  stauiing  of  syphilitic  bodies  in,  50. 

treatment,  356. 

loha  intramuscular  injection,  338. 
lonisation  in  Ulcus  molle,  368. 
Iris,  gumma  of,  rare,  155. 
Iritis,  congenital  syphilitic,  273. 

commoner  in  females,  273. 

treatment,  273. 

gonococcal,  422. 

syphilitic,  155. 

— ■ —  and  gonococcal,  compared,  155. 

effect     of     treatment     upon, 

compared,  155. 
Iron,  action  on  enzyme  action  in  nuclear  link, 

286. 

staining  of  nuclei  of  syphilitic  bodies  for 

content  in,  47. 

Iron  hydroxide,  without  action  on  sera,  77. 

Izar.     See  Ascoli  and  Izar. 

Jacobsthal,   optic    sero-diagnosis   of   syphilis, 

69. 
Jakob.     See  Weygandt  and  Jakob. 
Jaundice,  complicating  syphilitic  cholangitis, 

177. 

congenital  syphilitic  rare,  268. 

following  injection  of  salvarsan,  295. 

Jelly  method,  Ross's  application  in  study  of 

life-history  of  Spirochaeia  pallida,  5,  6. 
Jennings,  phases  in  development  of  Spirochaeia 

pallida,  5. 
Jews,  circumcision  compulsorj'  with,  464. 
Joints,  gonococcal  infection  of,  407. 

Hydrops  arliculi,  408,  410. 

syphilitic,  becoming  tilled  with  pus,  267. 

• See  also  Bones  and  joints. 

Kaolin,  effect  on  sera,  77. 

Kaplan,  amino-content  of  syphilitic  sera,  87. 

Kaplan's  Goldsol  curves.     See  Goldsol  curves. 

method  for  testing  presence  of  protein  in 

cerebro-spinal  fluid,  189. 

Kaposi's  axiom  as  to  diagnostic  sign  of  con- 
genital syphilis,  262. 

Kations,  effects  on  adsorptive  powers  of  electro- 
negative and  electro-positive  dyes,  26. 

Keratitis,  congenital  syphilitic,  interstitial 
double,  conditions  associated  with,  273. 

■ •  interstitial,  in  congenital  sj^jhiUs,  156. 

•  in  later  life,  diagnostic  of  congenital 

syphilis,  274. 

Keralodermia  blennorrhagica,  425. 

Kidneys,  congenital  syphilitic  disease  of,  270. 

diseases   of,   contraindicating   salvarsan, 

314. 


604 


INDEX. 


Kidneys,  diseases  of,  formation  of  paramino- 
(C  phenyl-arscnoxide,  225. 
Kieselguhr,  action  on  sera,  77. 
Kieselsdure,  without  action  on  sera,  77. 
KJausner,  precipitation  test  of,  69. 
Klingmtiller  and   Baermann,   syphilitic   virus 

not  a  filter  passer,  1. 
Knee-jerk,  loss  of  in  degenerative  myelitis,  247. 
Knee-joint,  gonococcal  infection  of,  408,  410. 
Korte,  de,  cause  of  syphilis,  3. 
Kreibich.     See  Lipschiltz  and  Kreibich. 
Kryzsytolowicz  and   Siedlecki,  life-history  of 

Spirochaeta  pallida. 
Laboratories,  public,  advocated,  497. 
Lallemand-Troussean  bodies  in  prostatitis,  392. 
Lange.     See  Wassennann  and  Lange. 
Lange's  method  (Goldsol  reaction)  for  testing 

presence  of  globulin  ia  oerebro-spinal  fluid, 

188. 
Lanugo  hair  follicles,  516,  522. 
Laryngeal  crises  in  degenerative  myelitis,  246. 
Lecitliin,  importance  to  life,  52. 

in  nerve  tissue,  50. 

— —  present  in  syphilitic  parasite,  50. 

■ — —  production  of,  53. 

Lecithin  globulin,  effect  on  reaction  when  added 

to  normal  serum,  80. 

on  sera,  normal  and  syphilitic,  79. 

• •  male  gametocyte  richer  than  female  in, 

57. 

phases  of  Leiicocytozoon  sypMlidis  rich  in, 

78. 

— ■ — ■  precipitation  necessary  before  extraction, 
of  fluid,  80. 

pure  action  on  complement,  79. 

Lecithm  -  globulin    complex,     phj'sical    and 

chemical  properties,  52. 

• — —  resistance  to  putrefaction  of  fluids  con- 
taining, 53. 

Lecithin-globulin  compound,  precipitation  of, 
52. 

relation  of  pseudo-globulin  content  to,  52. 

Lecithin-globulin  envelope,  505. 

V.  Leczcznysky's  method  of  staining  gonococcus, 
372. 

Leprosy,  positive  Wassermann  reaction  in,  100. 

Leptomeningitis,  gummatous  diffuse,  congenital 
syphilitic,  271. 

syphilitic,  238,  241. 

— content  of  cerebro-spinal  fluid  in, 

194. 

• of  brain  and  spinal  cord,  207. 

Leucaemia  ciUis,  545. 
lymphatic,  535. 

myeloid,  535. 

pseudo,  536,  542. 

Leucocyte,  basophUe,  582. 

eosinophile,  587. 

polymorphonuclear,  582. 


Leucocytes,  changes  of,  in  sjiphilis,  150. 

neutrophile,  in  syphilis,  effect  of  treat 

ment  upon,  150. 

mononuclear,  increase  of,  on  invasion  of 

body  with  syphilis,  83. 

large,   spirochaetae  developing   in, 

richer  in  lipoid  proteins,  57. 

polyjuorphonuclear,      in     cerebro-spinal 

fluid,  in  syphilitic  infections,  185. 

sign  of  degeneracy,  435. 

and  lymphocytes,  ratio  between,  in 

syphilis,  150. 
Leucocytozoon,  spiroohaetal  phase  of,  57. 
Leucoci/tozoon  syphilidis,  98,  230,  473. 
— - —  aberrant  development,  11,  200. 
in  sores,  127. 

action  of  salvarsan  on,  278,  279. 

annihilation  of,  120. 

arguments  against,  23. 

asexual  development  sore  formed  by,  120. 

asexual  stage,  9. 

mode  of  development,  127. 

biochemistry  of,  S3. 

chemistry  of,  25-54. 

destroyed  by  saprophytic  organisms,  123. 

development  in  asexual  stage  only,  12. 

of,  protective  response  of  host  to, 

129,  130. 

— Spirochaeta  pallida  in,  9. 

effect  of  entrance  of  male  gamete  into 

female  cell,  17. 

extension    of    polar    bodies     after    im- 
pregnation, 58. 

formation  of  protective  cells  by  host  after 

invasion  by,  126. 

invasion  of  nervous  system  by,  compared 

with  systemic  invasion,  202. 

lecithin  present  in,  50. 

life-cycle  of,  8,  136,  278. 

life-history,  119. 

male  phase,  extra-cellular  development, 

214. 

male  and  female  gametocytes  of,  9. 

not  pus  producing,  252. 

■ — ■ —  order  to  which  assigned,  10. 

phases  of,  499. 

congenital  syphilis,  275. 

in  brains  from  cases  of  degenerative 

encephalitis,  212. 

in  section,  ready  methods  for  differ- 
entiating between,  30. 

rich  in  lecithin  globulin,  78. 

— ■ situation  of,  in  brain,  210,  212. 

porportion   of   cases   in   which   nervous 

system  is  invaded  by,  201. 

pus  not  produced  by,  141. 

reaches  nervous  system  during  stage  of 

generalisation,  200. 

spores  of,  do  not  cause  inflammation,  121. 


INDEX. 


605 


Leucocytozoon  syphilidis,  spores   of,  infective, 

agent  of  syphilis,  126. 
spread  to  nervous  system,  219. 

sporozoite  of,  8. 

Leucoderma    colli    in    generalised    syphilis    in 

women,  255. 
Leucoderma  siiphililicuvi,  137. 

sex  incidence,  137,  138. 

Leucoplakia   followed    by,  but   not   cause    of 

carcinoma,  1(33. 
— - —  following  use  of  salvarsan,  302. 
origin  of,  103. 

of  tongue,  causes  of,  163. 

common  in  syphilis,  103. 

• — . conditions  producing,  163. 

Levaditi,  silver  nitrate  impregnation,  method 

of,  2. 
Levaditi's    silver   nitrate    method,    Noguchi's 

modification,    63. 
Lice,  haunts  and  treatment  of,  476. 
Lichen  planus,  affecting  glans  penis,  143. 

following  use  of  salvarsan,  302. 

Lightning  pain  in  degenerative  myelitis,  246. 
Lipoid,  increase  in  late  cases  of  syphilis,  84. 

substance  in,  producing  antigenic  action, 

71. 

Lipoid  cell  degeneration,  85. 

Lipoid  complex,  elaborate,  steps  necessary  for 
building  up  of,  55. 

Lipoid  degeneration  in  syphilitic  aortitis,  147. 

strong  Wassermaim  reaction  accom- 
panying, 148. 

Lipoid-globulin,  500. 

breaking  down  of,  300. 

complement  identical  with,  83. 

globulin  in  oerebro-spinal  fluid  existing 

in  form  of,  191. 

homologous,  formation  of,  how  effected, 

118. 
■ identity  of  reagin  with,  78,  79,  80. 

in  syj)hilis,  functions  of,  78. 

globulin  particles  in  excess  in  early 

stages,  01. 
lipoid  particles  more  numerous  in 

later  stages,  01. 
in  syphilitic  serum,  adsorptive  capacity, 

82. 

in  urine,  153. 

insolubility  of,  38. 

nature  and  distribution  of,  508. 

• of    serum    protective    substance    against 

syphilis,  258. 
. of  serum  of  women,  relation  to  that  of 

syphilitic  sera,  258. 
•  protective  agency  of,  217. 

protoplasm  of  plasma  cells  rich  in,  286. 

. pure,  isoelectric,  86. 

reagui  in  all  cases  of  syphUis  a,  61. 

. •  richness  of  nerve  tissue  in,  214. 


Lipoid-globulin,   specific,  productive  in  host, 
110,  117. 

specificity  in,  on  what  dependent,  258. 

vital  part  of,  83. 

cirrhosis  of,  .syphilitic,  177. 

how   distinguished   from   alcoholic, 

179. 

congenital  miliary  gummata  of,  269. 

syphilitic    alcoholic    extract,    best 

form  of  antigen,  65. 

disease  of,  268. 

contraindicating  salvarsan,  313. 

foetal,  syphilitic  use  as  antigen,  09. 

formation  of  blood  by,  capacity  retained 

in  congenital  syphilis,  274. 

Spirochaeia  pallida  in,  269. 

syphilitic,  diseases  of,  177. 

early    administration     of     neo-sal- 

varsan  important  in,  177. 
Lipoid-globulin  complexes,  506,  531. 

mode  of  action,  83. 

molecules,  effect  of  successive  salvarsan 

injections  on,  94. 

in  serum  of  pregnant  women,  95. 

lipoid  portion  greater  in   late  cases  of 

syphilis,  94. 

particles,  complement,  probably  in  normal 

serum,  antibody  in  sypliilitic,  82. 

Lipoid  nitrogen,  estimation  in  syphUitic  sera 

cannot  be  made,  84. 
Lipoid-protein content  of  Spirochaeia  pallida,  57. 
Lipoid-proteins,  adsorptive  capacity,  86. 
•  complexes,  287. 

nerve-cells  rich  in,  57. 

Lipoids,  carriers,  of  ferments,  286. 

increase  in  cerebrospinal  fluid  ui  syphi- 
litic cerebral  disease  of,  192. 

Lipschiitz,  Ulcera  pseudo-i^enerea,  254. 

and  Kreibich,  infective  granules,  4. 

Lithium  carbonate,  action  on  nuclei  of  syphilitic 

bodies  and  on  herring's  roe  compared,  44. 
Liver,  acute  j'cllow  atroph}-  of,  syjjhilitic,  177. 
Look  Hospital,  London —  treatment  at,  498. 
Loeb,  chemistry  of  fertilisation,  18. 

staining  of  fertilised  ovum,  17. 

Louse,  crab  (Phthirius  inguinalis),  470. 
Ludyl,  282. 

treatment  with,  347. 

Luetin  reaction,  negative,  in  untreated  cases 
of  sjfphilis,  114. 

positive  in  cases  of  .syphilis  after  triat- 

ment,  114. 

results  in  degenerative  encephalitis  and 

myeUtis,  114. 

Lumbar    puncture,    relieving    compression   in 

syphilitic  pachymeningitis,  224. 
Lumbar  puncture  needles,  Barker's,  182. 
Lung  tissue  extract,  in  diagnosis  of  recurrent 

and  congenital  syphilis,  115. 


606 


INDEX. 


Lungs,  congenital  syphilitic  disease  of,  268. 

syphilitic  disease  of,  areas  affected,  167. 

diagnosis  difficult,  167. 

• by  X-rays,  168. 

—  effect  of  salvarsan  on,  168. 

special  nature  of,  168. 

Lupus  vulgaris  and  syphilis,  differentiation  of 

facial  scars  arising  from,  140. 
Lustgarten's  bacillus,  1. 
Lymphadenitis    accompan3ring    intra-urethral 

chancre,  131. 

treatment  of,  369. 

Lymphadenoma,  536. 
Lymphadenosis,  536. 

— ■ — ■  chronic,  540. 
inflammatory,  538. 

malignant,  539. 

Lymphangitis,  occurrence  after  development  of 

primary  sore,  122. 
^—  of  penis;  367,  368. 
— — •  phagedaenio  chancres  unaccompanied  by, 

122. 

syphilitic,  144. 

— - — ■  causing  oedema  of  skin  of  penis,  144. 

■  late,  145. 

•  with  enlargement  of  scrotum,  145. 

LymphangioendotheMomata,  578. 

Lymphangioraata,  578. 

Lymphatic  glands,  degree  of  enlargement  and 

lymphocyte  count,  151. 

effect  of  presence  of  phagedaenio  ulcers, 

122. 

— ■ —  enlarged    protective    capacity    of    host 
against  parasite  better,  144. 

enlargement  of,  528,  537. 

after  development  of  primary  sore, 


hardness,     in     diagnosis     of 


122. 
and 

chancre,  125. 
in  congenital  syphilis,  273. 

in  neck,  enormous  enlargement  due  to 

syphilitic  invasion  explained,  144. 

infected,  removal  discountenanced,  122. 

inguinal,  changes  in  syphilis,  121. 

enlarged  iris  and  infection,  132. 

large  and  soft,  and  small  and  hard,  histo- 
logical findings  compared,  130. 

— ■  lymphocytes  manufactured  in,  position 
of,  151. 

removal  of,  322. 

— -  suppuration  after  svi^liilitie  invasion,  145. 

syphilitic,  enlarged,  144. 

hard  and  discrete,  144. 

— •  — ■ — •  impUcation  greatest  in  neighbour- 
hood of  primary  sore,  144. 

•  and  normal,  estimation  of  chloride 

content,  87. 

total  infection  after  syphilitic  invasion, 

122. 


Lymphatic  leucaemia,  535. 

Lymphatic  system  of  peripheral  nerves  aspath 

of  infection  to  central  nervous  system,  208. 
Lymphatic  vessels,  lymphocytic  formation  of, 

527. 
Lymphocyte  chart,  prognosis  of  syphilis  from, 

151. 
Lymphocyte  count  and  degree  of  enlargement 

of  lymphatic  glands,  151. 

in  males  and  females  compared  in  syphilis, 

151. 

in  syphilis,  150,  151. 

in  severe  and  mild  cases,  compared, 

150,  151. 

relative  in  negro  and  white  man  compared 

in  syphilis,  150. 

Lymphocytes  and  polymorphonuclear  leuco- 
cytes, ratio  between  in  sypliiUs,  150. 

cell  which  delvelops  from,  529. 

embryo,  in  cerebro-spuial  fluid  in  syphi- 
litic degenerative  lesions,  168,  187. 

formation  in  lymphatics,  spleen  and  bone 

marrow,  537. 

function  of,  529. 

in  cerebro-spinal  fluid,  in  syphilitic  infec- 
tions, 185,  186. 

origin  of,  187. 

in  syphilis,  effect  of  treatment  upon,  150. 

manufactured  in  lymphatic  glands,  posi- 
tion of,  151. 

origin  of,  526. 

part  played  in  disease  bj',  534. 

partial  source  of  reagin  in  cerebro-spinal 

fluid,  193. 

reaching  circulation,  source  of,  151. 

rCile  of  in  sarcoma,  538. 

small,  staining  of,  contrasted  with  that 

of  nuclei  of  parasitic  bodies,  41. 

and  sporozoitic  resemblance  be- 
tween staining  of,  41. 

— ■ — •  source  of  protective  substances  in  host 
against  syphilis,  151. 

staining  characters  of,  528. 

Lymphocytic  growth,  544. 

Lymphooytoma,  cutaneous,  very  strong  posi- 
tive Wassermann  reaction  in,  97. 

endothelial,  547. 

leucaemic  and  aleucaemic,  cause  of,  98. 

Lymphocytomata,  543. 

leucaemic  and  aleucaemic,  syphilis  cause- 

of,  151. 

of  skin,  560. 

svpliilitic,  occurrence  of  amphoteric  sera 

in,  73. 

Lymphocytosis,  cerebro-spinal  fluid,  205. 

— —  in  syphilitic  lesions,  effect  of  treatment 

on,  187. 
Lymphodermia  pemiciosa,  543,  555. 
Lymphogranulomatosis,  550,  553,  555. 


INDEX. 


607 


Lymphosarcomatosis,  545. 

Lyniphopoetic  system,  syphilis  of,  144. 

Lysine,  test  for,  46. 

McDonagh's  intravenous  syringe,  343. 

Mackintosh  and  Fildes,  hypersensitiveness 
theory  of  late  syphilitic  lesions  of  brain, 
230. 

MoLeod  and  Soga,  method  for  cultivation  of 
spiroohaetae  under  anerobic  conditions,  62. 

Maculae  coeriileae,  476. 

Macule,  syphilitic,  135. 

Maculo-papules,  syphilitic,  on  trunk,  leading  to 
atrophy  of  skin,  138. 

Magnesium  carbonate  in  balanitis,  467. 

Magnesium  sulphate,  action  on  nuclei  of 
sj-philitio  bodies  and  on  herring's  roe  com- 
pared, 43. 

Malaria,  positive  Wassermann  reaction  in,  100. 

tertiary  syphilitic  fever  diagnosed  as,  178. 

transmission    of,    not    comparable    with 

that  of  syphilis,  24. 
Males    and    females,    lymphocyte    count     in 

syphilis  compared,  151. 
Malignancy,  two  kinds  of,  524. 
Malignant  disease,  relationship  of  inflammation 

to,  499. 

n'lle  of  cells  in  causation,  580. 

theory  as  to  origin,  98. 

Malthusian  appliances,  495. 
Marriage  and  gonorrhoea,  490. 

syphilis  and,  485,  490. 

time  to  elapse  after  infection,  487. 

when    permissible   to    men,    subjects    of 

syphilis,  257. 

Massage  of  seminal  vesicles,  400. 

Mast  cell  granules,  nature  and  function,  206. 

Mast  cells,  583. 

activity  of,  587. 

granides,  staining  of,  584. 

relation  to  supply  of  pigments,  286. 

Masturbation,  sexual  neurasthenia  caused  bv, 

478. 
Medulla,   inflammatory   involvement   of,    171. 

172. 

See  also  Osteomyelitis,  syphilitic. 

Meier.     See  Porges  and  Meier. 
Meiostagmine  reaction,  70. 

Meirowsky,  characters  of  SjiirocJiaeta  pallida,  2. 

use  of  extract  of  syphilitic  lives  in  cuti- 

reaction  of  syphilis,  113. 

Melanoma,  malignant,  578. 

Men,  reason  why  syphilis  less  severe  in  women 

than  in,  151. 
Men  and  women,  difference  between  syphilis  in, 

257. 

no  difference  in  primary  lesions  of  sy- 
philis between,  257. 

Meniere's  symptom  complex,  following  syphilis, 
161. 


Meningeal  lesion,  syphilitic,  diagnosis  from  de- 
generative lesion,  186. 

Meninges,  cerebral,  topographical  anatomy  of, 
210. 

path  of  invasion  by  syphilitic  organisms, 

210. 

syphilis  of,  curability,  212. 

syphilitic,  infection  of,  spreading  to  nerve 

matter,  215,  217. 

inflammation      of,      followed      by 

cranial  nerve  lesions,  211. 

lesions  of,  curability  under  pro- 
longed drastic  treatment,  220. 

Meningitis,  cerebral,  syphilitic,  241. 

cerebro-spinal  syphilitic,  241. 

blood  in  cerebro-spmal  fluid  in,  18S. 

spinal,  syphilitic,  241. 

treatment  of,  334. 

streptococcal,  total  nitrogen  in  cerebro- 
spinal fluid  in,  192. 

syphilitic  basal,  case-history,  233,  234. 

death  following  second  injection  of 

salvarsan,  234. 

complications,  233. 

cerebro-spinal,  case   liistorics,  234. 

proportion  of  cases  showing  signs 

or  symptoms  of,  201. 

treatment  of,  328. 

Wassermann  reaction  in,  104. 

tubercular,  total  nitrogen  in  cerebro- 
spinal fluid  in,  192. 

Meningo-enccphalitis,  acute,  blood  in  cerebro- 
sjjinal  fluid  in,  185. 

inflammatory,  reaction  in,  318. 

syphilitic,  238. 

content  of  cerebro-spinal   fluid   in. 

194. 
degenerative,  periods  of  quiescence 

in,  222. 
development   in   eases   of   severest 

cutaneous  maniJfestations,  203. 

diffuse,  238. 

localised,  239. 

symptoms,  239. 

treatment  of,  330. 

Meningo-myeHtis,  syphiUtic,  242. 
course  of,  242. 

degenerative  and  non-degenerative 

often  co-existent,  243. 
syphilitic,  development  of,  in  cases 

of  severest  cutaneous  manifestations,  203. 

symptoms,  242. 

Mercurial  inunction,  352. 

pEls,  354. 

stomatitis,  3.54. 

suppositories,  353. 

Mercurialism,  355. 

Mercuric  chloride  as  fixing  reagent  in  staining 
of  syphilitic  organisms,  32. 

2  Q 


608 


INDEX. 


Mercury,  action  as  catalyser,  290. 

effect  on  absolute  and  relative  lympho- 
cyte count  in  syphilis,  151. 

— globulin  excretion  in  urme,  152. 

of  treatment  with,  355. 

formation  of  antibodies  not  checked  by, 

141. 

— — •  hastens  disappearance  of  sj-mptoms  of 
primary  syphilis,  122. 

Herxheimer's  reaction  after,  303. 

in  congenital  syphilitic  interstitial  kera- 
titis, 273. 

in  excess,  syphilitic  disease  of  bones  and 

joints  aggravated  by,  169. 

in   treatment   of   syphilis,    influence    on 

Wassermann  reaction,  106,  107,  108,  110. 

internal  treatment  with,  353. 

intramu-scular  injections  of,  350. 

intravenous  injections  of,  349. 

no  improvement  under,  in  aberrant  form 

of  syphilis,  14. 

oral  administration,  effect  on  tongue,  163. 

prolonged  administration  after  salvarsan 

injections  in  syphilis  essential,  123. 

— •  salvarsan  not  supiilemented  by  harmful, 
123. 

treatment    by    checking    production    of 

antibodies,  219. 

—  development  of  degenerative  sy- 
philitic nervous  lesions  after,  219. 

— ■ —  poh'neuritis  following  but  not  due 

to,  231. 

prolonged,   after  several  injections 

of  salvarsan,  effects,  220. 

Mercury  and  iodides  sujiplementary  to  sal- 
varsan treatment  of  syphilis.  111. 

and  salvarsan  combined,  in  treatment  of 

syphiUtic  optic  neuritis,  1.57. 

■ —  effect     on     syphilitic     neuritis     of 

cranial  nerves,  160. 

Merozoite,  19. 

definition  of,  10. 

Merozoites,  sexual,  development  of  trophozoite 
into,  56. 

number,  formed  variable,  56. 

Metals,  action  on  oxidising  enzymes,  286. 

and  non-metals,  arsenic  on  border 

between,  277. 

Methyl  green  compared  with  pyronin,  30. 
— ■ —  positively  charged  colloid,  20. 

specific  action  for  chromatin,  30. 

— —  staining  action  facilitated  by  anions, 

staining  of  syphilitic  organisms  with 

Methyl  green  and  methylene  blue,  comparison 

between,  30. 

and  pyronin.     See  Pappenheim's  stain. 

Methylene  blue  and  methyl  green,  comparison 

between,  30. 

See  also  Borax  methylene  blue. 


line 


27. 
31. 


Methylene  red,  staining  of  syphilitic  organisms 
with,  31. 

use  for  obtaining  in  vivo,  28. 

Methylene  stains,  502. 

Methylene  violet,  reduction  sensitive  dye,  31. 
ML'tritis  following  gonorrhoea,  255. 

syphilitic,  question  of,  255. 

Metrorrhagia  following  gonorrhoea,  255. 
Metrorrhagia  neoiialortim,  270. 
Metschnikoft's  ointment,  495. 
Michaelis,  precipitation  test,  69. 

Milia  present  in  epitheliomata,  515. 

Milian,  adrenalin  as  remedy  against  untoward 
symptoms  of  salvarsan,  226. 

Milky  effusions,  production  of,  53. 

Millon's  reagent,  staining  of  syphilitic  sections 
with,  38. 

Mole  cells,  567. 

Moles,  565,  568. 

Molluscum  contagiosum,  468,  499. 

Monoplegia,  syphilitic,  147. 

Moolgavkar,  phases  in  development  of  Spiro- 
chaela  paUirIa,  5. 

Morpliology  of  little  help  in  differentiation  of 
bacilli,  60. 

Mother  and  father,  syphilis  in,  relative  import- 
ance, 250. 

Mothers,  syphilitic  infants  born  without  posi- 
tive Wassermann  reaction  in,  250. 

treatment  during  whole  of  preg- 
nancy, result,  251. 

Mouneyrat,  preparation  of  gahl  and  ludyl, 
282." 

Mouth,  mucous  membranes  of,  syphilitic 
papules,  erosions  and  ulcers  of,  267. 

syphilis  of,  162. 

Mucous  membranes,  congenital  syphilitic  dis- 
ease of,  267. 

Mtihlens  and  Hoffmann,  cultivation  of  spiro- 
chaetae,  60. 

Muscles,  gonococcal  infection  of,  412. 

injections  into,  advantages  of  intra- 
venous injections  over,  345. 

Muscular  pain  following  injection  of  salvarsan, 

298. 
Mycosis  fungoides,  543,  545,  550. 

classification  of,  551. 

clinical  characteristics,  552. 

histological  characters  of,  555,  557. 

Wassermann  reaction  in,  558. 

Myelitis,  congenital  syphilitic  degenerative,  271. 
•  symptoms,  271. 

degenerative,  480. 

result  of  luetin  reaction  in,  114. 

treatment  of,  336. 

syphilitic,    albumin    and    globulm 

content  in  cerebro-spinal  fluid  in,  189. 
content  of  cerebro-spinal  fluid 

in,  190. 


INDEX. 


609 


Myelitis,  degenerative,  syphilitic,  diagnosis  by 
Kaplan's  Goldsol  curves,  19(5-198. 

■  •  gastric  crises  of,  170. 

meningeal,     and    ameningeal 

orm,  244,  245. 

Opthalmoplegia  iiiienui,  symp- 
tom of,  158. 

spontaneous  cure  of,  196. 

• ■  Wassermann  reaction,  190. 

■  syphilitic,  degenerative,  244. 

■  case  with  .symptoms  of,  result 

of  treatment,  215. 

oerebro-spinal  fluid  in,  245. 

•  in    comiection    with    primary 

optic  atrophy,  236,  237. 

— ■  incurability,  212. 

•  involvement  of  cardiac  sym- 


pathetic nerves  in,  149. 
•  — - — •  not    preceded 


by    syphilitic 

lesions  of  nervous  system,  213. 
of  posterior  part  of  the  cord 

analogous    to    degenerative    encephalitis    of 

cerebral  cortex,  217. 
■ — ■ •  phases  of  leucocytozoon  found 

in  brains  from  cases  of,  212. 
preceded  by  vascular  lesions 

of  nervous  system,  213. 
replaces  terms  of  Tabes  dor- 

salis  or  locomotor  ataxv,  244. 

site  of,  210. 

spontaneous  cure,  222. 

symptoms,  245,  246,  247. 

VVassermann's  reaction  in,  245. 

haemorrhagic,    244. 

stages  of,  244. 

positive    Wassermann    reaction    in 

blood  in  cases  of,  218. 

retinitis  associated  with,  156. 

transverse,  analogous  to  hemiplegia, 

217. 
transverse  prodromal  and  sensory  symp- 
toms, 243. 
Myeloid  leucaemia,  535. 
Myers,  amount  of  calcium  in  sera,  87. 
Myocarditis,  diffuse  syphiUtic,  148. 

syphiUtic,  267. 

— — ■  of  left  ventricle,  149. 

Naevi,  565,  568. 

Naevo-xantho-endotheliomata,  568,  573,  577. 
Naevus  verrucosus,  572. 

Navy,  dimmution  of  venereal  diseases  in,  495. 
Neck,  lymphatic  enlargement  due  to  syphilitic 

invasion  explained,  144. 
Necrosis,  following  injection  of  salvarsan,  340. 
Negro,  total  increase  of  leucocytes  in,  compared 

with  that  of  white  man,  in  syphilis,  150. 
Neo-salvarsan,  279. 

admuiLstration  at  early  stages  in  syphi- 
litic diseases  of  liver,  177. 


Neo-salvarsan,  advantage  over  salvarsan, 
279. 

formula  of,  279. 

formula  when  injected,  280. 

in  syphilitic  pancreatitis,  180. 

in   treatment    of   syphilis,    influence   on 

Wassermann  reaction,  106. 

inflammatory  reaction  less  severe  with, 

319. 

injections  of,  effects  of,  295. 

intervals  in  treatment,  toxic  symptoms 

after,  302. 

intramuscular  mjection  of,  341. 

intravenous  injection  of,  344. 

■  reagent  agaiiist  Spirochaela  pallida,  280. 

therapeutic  action  compared   with   that 

of  salvarsan,  280. 

toxic  action  of,  301. 

toxicity  and  potency  of,  294. 

Nephritis,  balsamic,  382,  404. 

interstitial     chronic,      am\loid      disease 

supervening  upon,  153. 

usually  symptom   of   genera- 
lised arterio-sclerosis,  153. 
congenital  syphilitic,  270. 

syphilitic,  early,  rarity,  153. 

late,  progressive,  153. 

Nerve,  auditory,  sj'philitic  neuritis  followed  by 
deafness,  159. 

optic,  atrophy  of  in  congenital  syphilitic 

degenerative  myelitis,  271. 

■  primary,   in  connection   with 

degenerative  myelitis,  236,  237. 
Nerve  cells,  derivation  of  reagui  from,  78. 

medium    for    development    of    s\'philitic 

organisms,  221,  222. 

Nissl,   bodies  of,   destruction  of  affinity 

for  basic  dyes,  26. 

rich  in  lipoid  proteins,  57. 

Nerve  lesions,  syphilitic  degenerative,  effect  of 
treatment  on  Wassermann  reaction.  111. 

Wassermann  reaction  in,  104. 

Nerve  matter,  syphilitic  hifection  of  meninges 
spreadmg  to,  215,  217. 

Nerve  roots,  spinal,  syphilitic  inflammatory 
changes  in  perineural  sheaths  of,  207,  208.   ■ 

Nerve  tissue,  lecithin  in,  50. 

richness  in  lipoid  globulins,  214. 

syphilitic   affections   of,   dependence   on 

primary  venous  lesions,  212. 
Nerves,  cardiac,  sympathetic,  involvement  in 

degenerative  myelitis,  149. 
cranial,  paralysis  of,  congenital  syphilitic, 

272. 

• syphilitic  lesions  of,  236. 

yield  to  early  and  adequate 

treatment,  211. 
neuritis,   effect   of   treatment 

upon,  160. 

2   Q    2 


610 


INDEX. 


Nerves,  peripheral,  lymphatic  system  of,  as 
path  of  infection  to  nervous  system,  208. 

■ syphilis  of,  231. 

■ syphilitic  inflammatory  changes  in 

connective  tissue  coverings  of,  207,  208. 

lesions  of,  aifect  both  motor 

and  sensory  nerves,  211. 

Nervous  system,  arterial  lesions,  201. 

diseases  contraindioating  salvarsan,  315. 

gonorrhoea  of,  413. 

invasion  by  syphilitic  organism,  com- 
pared with  systemic  invasion,  202. 

lesions  of,  blood  in  cerebro-spinal  fluid 

resulting  from,  184. 

parasyphilitic  affections,  countries  where 

rare,  229. 

why  increasing,  230. 

progressive  degenerative  changes  in,  158. 

proportion  of  cases  in  which  syphilitic 

organism  invades,  201. 

stage  of  syphilis  during  which  leucocyto- 

zoon  reaches,  200. 

stoppage  of  supply  of  antibodies,  to,  219. 

syphilis  of,  489. 

^ biology,  200. 

clinical  aspect,  231. 

early  inspection,  clinical  evidence, 

before  and  after  treatment,  202,  203.  * 

• of  early  infection,  pathological  evi- 
dence, before  and  after  treatment,  205,  206. 

inflammatory  reaction,  307. 

nucleinate  of  soda  ui,  357. 

treatment  of,  328. 

Wassermann  reaction  in,  104. 

syphilitic  invasion  of  percentage  of  cases 

attacked,  217. 

lesions  of,  classification,  207. 

— —  degenerative,    frequency     in- 
creasing, 230. 
early  vascular,  213. 

central,  congenital  syphilitic  degenerative 

lesions,  fatal,  274. 

diseases  of,  271,  272. 

• degenerative  syphilitic  lesions  fol- 
lowing treatment  by  mercury,  219. 

■ haematogenous     as     distinguished 

from  lymphogenous  infection,  208. 

■  mctaluetio    lesions,    avoidance    of 

term,  216. 

sj'philitic  degenerative  lesions,  de- 
velopment of,  221. 

diseases  of,  216. 

how  to  avoid  symptoms,  227. 

influence  of  treatment  upon, 

217. 

meningeal,  216. 

neurotropic  origin,  228,  229. 

■ no  evidence  of  selective  action 

of  organisms,  230. 


Nervous  system,  central,  syphihtic  degenera- 
tive lesions,  percentage  in  persons  contract- 
ing syphilis,  228. 

. symptoms    on    the    increase, 

217. 

syphilitic  invasion  of,  date  of  onset, 

"217. 

syphilitic  lesions  of  compared  with 

cutaneous  lesions,  214,  215. 

factors  influencing  develop- 
ment, 220,  221. 

haematogeneous   origin,    212, 

213,  214. 

— • neither    wholly    degenerative 

nor  wholly  non-degenerative,  215. 

symptoms  of,   occurrence   at 

early  stage,  218. 

paths  and  sites  of  uifection, 

207,  208. 

primary,  236. 

secondary  origin,  232,  233. 

symptoms  of,  218. 

Neurasthenia,  gonorrhoea!,  480. 

sexual,  causes  of,  480. 

Herj^es  genitalis  causing,  478. 

prostatorrhoea  in,  397. 

syphUitic,  480,  482. 

Neuritis,  brachial,  sj-philitic,  232. 

foUowtng  salvarsan,  309. 

of  spinal  nerve  roots,  syphilitic,  232. 

optic,  complicating  syphilitic  basal  menin- 
gitis, 233,  234. 

• complicating  syphilitic  cerebro- 
spinal menmgitis,  234,  235,  236. 

in   syphilitic   meningo-encephalitis, 

239. 

■  syphilitic,  157. 

bilateral  and  unilateral,  157. 

treatment  by  salvarsan  and 

mercury  combined,  157. 

peripheral,  413. 

syiAilitic,  231,  481. 

Neuro-reourrences  after  salvarsan,  308. 
Neutral  emulsion,  preparation  of,  338. 
New-born,  gonococcal  conjunctivitis  in,  422. 
Nicolas  (and  others),  experiments  with  glycerin 

extract  of  foetal  syphilitic  liver,  113. 

Nicol's  prisms,  appearance  of  syphilitic  cells, 
under  use  of,  49. 

van  Niessen,  discovery  of  Syphilomyces  by,  1. 

Nile  blue  sulphate,  stauiing  of  syphilitic  bodies 
with,  50. 

Ninhydrin  inaction,  positive,  given  by  syphi- 
litic serum  in  presence  of  complement,  96. 

given    by    syphilitic    serum     with 

placental  extract,  95. 

Xissl's  bodies  of  nerve  cells,  destruction  of 
affinity  for  basic  dyes,  26. 

Nissl's  granules,  constitution  of,  78. 


INDEX. 


611 


Nitrogen,  increase  in  cerebro-spinal  fluid  during 

death  agony,  85. 
in  sypliilitic  sera,  84. 

natural  proteins  in  scrum  only  react  with 

trace  of,  88. 

time  taken  to  give  o(i,  by  various  amino- 

derivatives,  87. 

total  in  cerebro-spinal  fluid  m  disease, 

192. 

relation  to  Wassermann  reac- 
tion, 192,  193. 

in  normal  cerebro-spinal  fluid,  192. 

valencies  of,  in  relation  to  arsenic,  277. 

Nodules  of  Trichoe pithelioma  papillosum,  515. 
Noguchi,  cultivation  of  Spirochaeta  pallida,  59, 

60. 

preparation  of  luetin  by,  113. 

Spirochaeta  calligyriiiii,  60. 

Noguchi's    moditication    of    Levaditi's    silver 

nitrate  method,  63. 
Noguchi's  test  for  globulin  in  cerebro-spinal 

fluid,  188. 
Nonne,  blood  in  cerebro-spinal  fluid  in  case  of 

syphilitic  meningo-encephaUtis,  184. 
Nonne-Apelt's  reaction,  187. 
Nose,  perichondritis  of,  in  acquired  syphilis, 

165. 
Notification  of  venereal  diseases,  494. 
Nuclei,  contents  of,  286. 
Nuclein,  transformation  of,  505. 
Nucleinate  of  soda,  injections  of,  357. 
Nucleolus,  description  of,  50C. 

function  of,  505. 

Nuoleo-protein,  45. 

of  nucleus  of  syphilitic  bodies,  42. 

protein  radicle  of,  45. 

Nucleus,  accelerator  of  enzyme  action  in,  286. 
Oedema  of  skin  of  penis  set  up  by  syphilitic 
lymphangitis,  144. 

• toxic,  after  injection  of  salvarsan,  339. 

Oesophagus,  syphilis  of,  174. 

—  recovery  under  treatment,  174. 

syphilitic  stenosis  of,  174. 

Oleic  acid,  action  on  complement,  79. 
Onychia,  syphilitic,  264. 
Ophthalmoplegia,  external,  syphilitic,  158. 
■  degenerative,   158. 

internal,  syphilitic,  157,  158. 

significance  of  pin-point  pupils 

in,  158. 
symptoms     of     degenerative 

myelitis,  158. 

•"  syphilitic,  157,  158. 

Ophthalmoscope,    in    diagnosis   of   congenital 

syphilis,  274. 
Optic  nerve,  toxic  action  of  atoxyl  on,  281. 
Optic  neuritis,  after  salvarsan,  309. 
Orchitis,  sign  of  congenital  syphilis,  274. 
Oriental  sore,  diagnosis,  143. 


Orr  and  Rows,  path  by  which  infection  is 
carried  to  nervous  system,  208,  209. 

Osteitis,  syphilitic,  inseparable  from  syphilitic 
periostitis,  170. 

•  See  also  Osteoperiostitis,  sy- 
philitic. 

Osteochondritis,       syphilitic,        hjdrarthrosis 

supervening  on,  266. 

■ syphilitica,  265,  266. 

•  - — •  incidence  of,  265. 

Osteomyelitis,     gummatous    of    dij^loe,    170, 

171. 
— ■ — •  syphilitic,  diagnosis  from  syphilitic  osteo- 
periostitis, 171. 

from  tubercular  form,  172. 

spontaneous  fracture  foUowmg,  172. 

Osteoperiostitis,  syphilitic,  170,  260. 

diagnosis  at  sarcoma,  171. 

from  syphiUtic  osteomyelitis, 

171. 

of  clavicles,  172. 

• of  flat  bones,  ]  70. 

of  long  bones,  170. 

effect  of  blood  supply  on,  171. 

Osteoporosis  (syphilitic   rarefaction  of  bones), 

266. 
Ovum,  staining  of,  during  and  after  fertilisation, 

18. 
Oxaluria,  378,  416. 

Oxidation  and  reduction,  Unna's  theory  of,  31. 
Oxydase  content  and  positivity  of  Wassermann 

reaction,  no  ratio  between,  98. 

ferments,  287. 

reactions,  disappearance  upon  destruction 

of  complement,  83. 

in  cerebro-spinal  fluid,  192,  287. 

Oxydases,   lipoid-globulin   complexes,  vehicles 

for  oxydases,  82. 

relation  of  complement  to,  82,  83. 

Oxygen,  how  conveyed  to  tissues,  286. 

necessary   in   fertilisation   and   develop- 
ment of  zygote,  17. 
"  Oxj'gen  chain,"  links  in,  286. 

nature  of,  285. 

Oxygen  ferments  carried  by  lipoid -globulins  in 
syphilis,  78. 

carriers  of,  286. 

Pachymeningitis,  gummatous  diffuse,  con- 
genital syphilitic,  271. 

gwnmosa,  238. 

haemorrhojica     blood     in    cerebro-spinal 

fluid  in,  185. 

inflammatory  reaction  in,  317. 

late  symptoms  of  syphilis,  184. 

syphilitic,  237,  241. 

cause    of    persistent    headache    in 

later  stages,  238. 
compression    and     unconsciousness 

relieved  by  lumbar  puncture,  224. 


612 


INDEX. 


PachjTueningitis,  syphilitic,  content  of  cerebro- 
spinal tiuid  in,  194. 
Pain  in  degenerative  myelitis,  246. 
Palate,  hard,  syphilitic  periostitis  of,  165. 

perforation  of,  diagnostic  of  syphilis,  266. 

Pallidin,  effect  of   injection    of   tuberculin    in 

syphilitic  subject  followed  by  injection  of,  117. 

lung  extract  used  in  diagnosis  of  syphilis, 

115. 

Palms  of  hands,  rash  of  congenital  syphilis 

specially  affects,  262. 
Pancreas,  congenital  s\'philitic  disease  of,  269, 

270. 

syphilitic  disease  of,  179. 

Pancreatitis,  syphilitic,  179. 

case-history,  179,  180. 

•  treatment,  180. 

Pandy  reaction  for  testing  presence  of  protein 
in  cerebro-spinal  fluid,  189. 

Panosteitis,  syphilitic,  171. 

Papilloma,  types  of,  510. 

Pappenheim,  aleucaemia  of,  536. 

• specific  action  of  methyl  green  for  chro- 
matin, 30. 

Pappenheim's  method  of  staining  gonococcus, 
372. 

Pappenheim's  stain,  531. 

use  for  syphilitic  bodies,  31. 

use  in  preparation  of  sections  of  syphilitic 

organisms,  33,  34. 

Papular  lesions,  syphilitic,  137. 
Papule,  chancres  almost  always  commence  at, 
128. 

syphilitic,  135. 

degeneration     with     formation     of 

crust,  136. 

retrogression  of,  136. 

Papules,  clmical  appearance  varies  according 

to  localisation,  138. 
— —  mucous,  syphilitic,  162. 

syphilitic,  recurrent,  scabbed,  139. 

Papule -pustular  lesions,  syphilitic,  137. 
Paraffin,  use  in  preparation  of  sj^ihilitic  speci- 
mens, 33. 

Paralysis,  congenital  syphilitic,  272. 

facial,  imilateral  syphilitic,  161. 

general,  of  insane,  as  Ij-niphogenous  in- 
fection, 209. 

in  degenerative  myelitis,  245. 

Paramino-phenj-l-arsenoxide,  formation  of,  in 

relation  to  kidney  disease,  225. 

toxic  action,  224,  225. 

Paraphimosis  externa,  462. 

Paraphimosis  interna,  462. 

Paraplegia,  syphilitic,  243. 

See  also  Myelitis,  transverse. 

Parasite,  syphilitic,  pyroninophile  substance, 
and  colloidal  particles  of  pseudo-chylous 
iiuid,  close  resemblance  between,  53. 


Parasites  of  cancer,  so-called,  description  of,  506. 
Parasyjihilis,  avoidance  of  terra,  216. 
Paraurethritis  gonorrhoica,  391. 
Parents,  syphilitic,  healthy  children  by  after 
proper  treatment  of,  261. 

treatment  advisable  after  birth  of  syphi- 
litic child,  257. 

Parrot,  congenital  syphilitic  enlargement  of 
spleen,  270. 

gelatinous  atrophy  affecting  skull  bones, 

266. 

Parrot's  nodes,  266. 

Pediculus  pubis,  476. 

Pemphigus,  congenital  syphilitic,  fatal,  274. 

streptococcal,  263. 

syijhUitic,  263. 

syphiliticus  neonatorum,  263. 

Penis,  contiguous  chancres  on,  129. 

diseases  of,  461,  464,  467. 

erections  of,  impaired,  480. 

gangrene  of,  466. 

• Induratio  jyetiis  plastica,  474. 

locality  of  simple  papulo-ulcerative  chan- 
cre on,  130. 

lymphangitis  of,  367,  368. 

oedema  of  skin  of,  set  up  by  sj'philitic 

lymphangitis,  144. 

psoriasis  affecting,  143. 

skin  of,  button-chancre  on,  129. 

diffuse  papular  infiltration,  138. 

syphilitic  eruption  on,  diffuse,  papular, 

145. 

See  also  CofOHn  ;  Glans  penis. 

Pergenol,  use  of,  467. 

Perichondritis  of  nose  in  acquired  syphilis,  165. 
Pericranitis,  sj-philitic,  266. 
Perifolliculitis  gonorrhoica,  389. 
Perihepatitis,  syphilitic,  178. 
Periostitis,  gonococcal,  412. 

syphilitic,  165. 

inseparable  from  syphilitic  osteitis, 

170. 

See  also  Osteoperiostitis,  sy- 
philitic. 

of  hard  palate,  165. 

ossifjang,  266. 

Peripyle phlebitis  syphilitica,  269. 

Peritoneum,  syphilis  of,  180. 

affecting  tissue  subjacent  to,  176. 

Phagedaena,  362,  368. 

destruction  of  syphilitic  organism  by,  122. 

Phagocytosis,  rule  of,  367. 

in  inflammation,  580. 

Phenyloxyacetic    acid,    arsenic    derivative    of 

formula,  284. 
Phimosis,     accompanying     primary     sore     in 

corona,  131. 

acquired,  causes  and  treatment,  461. 

Phlebitis,  gonococcal,  415. 


INDEX. 


613 


Phlebitis,  syphilitic,  14(1. 

cases  of,  146. 

recurrent  local  asphyxia  of  fingers 

in  reality,  150. 
Phlegmonous  arthritis,  409. 
Phosphaturia,  378,  410. 
Phorphorus,  in  galyl,  283. 

staining    of    nuclei  of    sypliilitic    bodies 

for  content  in,  46,  47. 

Phthiriasis,  treatment  of,  477. 

Phihirius  iitduinalis,  476. 

Pia-arachiioid,  inflammation  of,  in  degenerative 

encephalitis,  210. 
Pigment,  formation  from  globulin,  507. 

production  of,  how  effected,  286. 

protective  mechanism,  286. 

Pigmented  endotheliomata,  566. 
Pills,  mercurial,  354. 

Pinkus,  pseudo-leucaemia  of,  536. 

Pituitary  body,  lesion  in.  Diabetes  insipidus  in 

congenital  syphilis,  272. 
Pityriasis  rosea,  differentiation  from  syphilis, 

142. 
Placental  extract,  factor  in  serum  of  pregnant 

women  necessary  to  break  down,  95. 

s\'philitic  serum  giving  positive  ninhydrin 

reaction  with,  95. 

Plasma  cell,  chemistry  and  physico-chemistry, 
285. 

crystalline  forms  of,  533. 

degenerate  forms  of,  532. 

function  of,  532. 

nucleus  of,  behaviour  on  degeneration,  44. 

origm  of,  529. 

protective    against    syphilitic    organism, 

285. 

Plasma  cells,  ballooned,  36. 

hyaline  masses  of,  502. 

See  also  A  mi  no- plasma  cells. 

in  cerebro-sptnal  fluid  in  syphilitic  de- 
generative lesions,  186,  187. 

part  played  in  disease  by,  534. 

protoplasm  of,  rich  in  lipoid-globulin,  286. 

Plasmosarconmtosis,  546. 

Plasmoma,  syphilitic,  histological  appearances 

after  salvarsan  treatment,  93. 
Plastcin,  531. 
Pleuritis,  syphilitic,  168. 
Pneumonia,  syphilitic  interstitial,  208. 

white,  of  Virchow,  268. 

Polar    bodies,    extension    from    Leucocytozoon 

syphilidis  after  impregnation,  58. 
PolJ^leu^itis,  syphilitic,  231. 
following,  but  not  due  to  mercurial 

treatment,  231. 

stage  in  whic^h  met  with,  232. 

Porges  and  Meier,  precipitation  test  of,  69. 
Potassium   iodide,   internal   administration   in 

CB,se  oi  (.'occidiosis  a  venerea,  19.  i 


Potassium  permanganate,  action  of  amino- 
acids  on,  37. 

staining  of  sections  of  syphilitic  bodies  in, 

35. 

Potency,  relationship  between  toxicity  and  of 
salvarsan,  294. 

Precipitation  and  hydrolysis,  Abderhalden's 
test,  process  of,  96. 

Precipitation  test,  in  diagnosis  of  syphilis,  69. 

Precipitation  theory  of  Wassermann  reaction, 
96. 

Pregnancies,  first  and  last  disastrous  in  syphi- 
litic parentage,  200. 

succeeding    birth    of    syphilitic    infant, 

treatment  during  essential,  250. 

Pregnancy,  Abderhalden's  test  for,  94. 

date  ijermitted  for,  after  paternal  syphilis, 

257. 

repeated,  effect  on  syphilis,  103. 

treatment   of   svphihtic    mother    during 

whole  of,  251. 

Pregnant  and  syphilitic  women,  sera  of  close 

resemblance  between,  95. 
Pressure,  plus  and  minus,   action  upon  sera, 

76,  77. 
Preventive  medicine  and  venereal  disease,  493. 
Proctitis  gonorrhoica,  404. 
Profeta's  law,  251. 
Prognosis  in  congenital  syphilis,  274. 

of  syphilis  from  lymphocyte  chart,  151. 

study  of  chancres  a  guide  to,  129. 

Prostate,  abscess  of,  393. 

gonococcal  infection  of,  392,  396. 

Prostatitis,  379,  381. 

chronic  symptoms  of,  394. 

treatment  of,  396. 

complicating  gonorrhoea,  391. 

Prostatorrhoea,  397,  481. 
Prostato-urethritis,  380. 

treatment  of,  395. 

Prostitutes,  registration  of,  494. 
Protagon,  action  on  complement,  80. 
Protamine,  503. 

Protargol  in  treatment  of  gonorrhoea,  384. 
Protective   substances   becoming   parasitic   on 

host,  97. 
Protein,  albumoses,   degeneration  products  of, 

88. 

examination  of  urine  for,  152,  153. 

in  cerebro-spinal  fluid,  187. 

examination,  187. 

excess  of,  191. 

influence  of  treatment  on,  192. 

in  urine  in  acute  stage  of  syphilis,  152. 

of  syphilitic  bodies,  39. 

behaviour  of  in  presence  of  various 

acids,  39,  40. 

insoluble  in  water,  39. 

pyroninophile,  nature  of,  40. 


614 


INDEX. 


Protein  of  syphilitic  bodies.  See  also  Pijro- 
ninophile  substance. 

structure  of  Fischer's  theory  as  to,  88. 

Protein  metabolism,  degeneration  products  of, 

530. 
Proteins,  derivatives  of,  strong  reducing  agents, 
37. 

natural,  in  serum,  only  react  with  trace 

of  nitrogen,  88. 

Protoplasm,  fi.xed,  amphoteric  substance,  31. 
stains  best  with  acid  dyes,  31. 

in  oxygen  chain,  28(3. 

portion  of  syphilitic  bodies,  38. 

Protozoa,  intermediate  host  not  required  bv 

all,  2-t. 
V.  Prowazek,  life-history  of  Spirochaela  pallida, 
Pruritis  ani,  405. 
Pseudo-chylous   fluid   with   dextrose,   reaction 

obtained  under,  49. 
Pseudo-globulin  faction  of   serum,  relation  to 

lecithin  globulin  compound,  52. 
Pseudo-leucaemia,  536,  542. 
Pseudo-paralvsis,  sign  of  congenital  syphilis, 

274. 
Pseudo-tabes,  243. 
Psoriasis,  affecting  penis,  143. 

differentiation  from  syphilis,  143. 

squamo-papularsyphilide resembling,  143. 

Public,  instructions  to,  497. 

Public  health  and  venereal  disease,  493. 

Pulse  rate  in  syphilitic  cardiac  lesions,  149. 

Pupil  anomalies  in  congenital  syphilis,  272. 

— ■ meningo-myelitis,  242. 

in   syphilitic    mentngo-encephalitis, 

238,  239. 

less  frequent  in  degenerative  ence- 
phalitis, 241. 

Pupils,  pin-point  significance  in  syphilitic 
Ophthalmoplegia  interna,  158. 

Purpura  in  congenital  syphilis,  264. 

Pus,  not  produced  bv  Leiicoci/tozoon  syphilidis, 
141,  252. 

produced  by  Ducrey's  bacillus,  133. 

syphilitic  jomt  becoming  filled  with,  267. 

Pustule,  svphiUtic,  distmction  from  varicella, 

136. 
Putrefaction,    resistance    of    fluids    containing 

lecithin-globulin  complex  to,  53. 
Pyelitis  gonorrhoica,  403. 
Pyelonephritis  gonorrhoica,  403. 
Pylorus,  syphilis  of,  174,  175. 

recovery  from  under  salvarsan,  175. 

Pyogenic  infections,  diagnosis  of  extra-genital 

chancres  from,  132. 

phagocytosis  in,  581. 

Pyronin.  formula  of,  291. 

— —  methyl  green  compared  with,  30. 

stainmg  action  facilitated  by  anions,  27. 

staining  of  syphilitic  bodies  with,  31. 


Pyronin,  staining  with,  503. 

Pyronin  and  methyl  green.     See  Pappenheim's 

stain. 
PjToninophile  substances,  39,  40. 

nature  of,  45. 

of  syphilitic  organisms,  31. 

staining  of,  45. 

Rabbits,  experimental  sji^hilis  in,  condition  of 

inguinal  lymphatic  glands,  120,  121. 
Rashes,  gonococcal,  424. 

toxic,  425. 

RajTiaud's  disease  accompanied  bj^  spasmodic 
haemoglobinuria,  149. 

association  with  syphilis,  149,  150. 

Reactionary  inflammation,  303. 
Reactions  to  salvarsan,  299. 

Reagin,  action  of,  76. 

formation  of,  increased  by  cold,  89. 

identity  with  lipoid-globnlin,  78,  79,  80. 

in   cerebro-spinal   fluid   invading    blood, 

193,  194. 

origin  of,  78. 

source  of,  193. 

in  Wassermann  reaction,  source  of,  151. 

lipoid-globultn  in  all  cases  of  syphilis,  61. 

method  of  action,  86. 

nature  of,  78. 

origin  of,  78. 

reason  for  adsorption  of  complement  by. 


95. 


and  complement  molecules  homologous, 

96. 

Reagm  molecule,  action  of  salvarsan  on,  93. 

injured  by  inactivation,  76. 

lipoid-globultn   molecule   in    serum 

of  pregnant  women  comparable  to,  95. 

C[uestion  of  specific  action,  94. 

Rectum,  gonococcal  infection  of,  404. 

gummatous  ulceration  of,  177. 

syphilitic  stricture  of,  177. 

sex  incidence,  177. 

Reduction  and  oxidation,  Unna's  theory  of,  31. 

Relapsing  fever,  effect  of  salvarsan  on,  5. 

Resorcinol  solutions,  use  in  preparation  of 
specimens  of  s>-philitic  organisms,  33. 

Retinitis,  syphilitic,  156. 

associated  with  choroiditis,  156. 

associated  with  syphilitic  myelitis, 

156. 

Rhmoscleroma,  aminoplasma  cells  met  with  in, 
36. 

Rhouiberg's  sign  in  degenerative  myelitis,  247. 

Rickets  and  congenital  syphilis,  simulate  one 
another,  266. 

Ricord's  pill,  354. 

Rodent  ulcer,  510,  514. 

Rongalit  white,  action  of,  30. 

Roseola,  congenital  svphiUtic,  practically  un- 
known, 263. 


INDEX. 


615 


Roseola,  syphilitie,  135. 

Ross,  E.  H.,  jelly-method  of,  .5,  C. 

phases    in    development    of    SpirocJiaeta 

pallida,  5. 

Royal  Commission,  aims  of,  400. 

"  Saddle-nose,"  267. 

Saline,  dilution  of  syphilitic  sera  with.  74. 

injection  after  withdrawal  of  cerebro- 
spinal fluid,  183. 

Salpingitis,  gonococcal,  431. 
Salts  in  normal  serum,  effect  on  Wassermann 
reaction,  86. 

influence  on  process  of  fertilisation,  18. 

Salvarsan,  action  of  on,  Leucocytozoon  si/pltiliilis, 

278. 

on  lipoid-globulin  in  urme,  152. 

■ on  reagin  molecule,  93. 

administration    of,    erythema    following, 

224. 

followed  bj-  haemorrhagic  en- 
cephalitis, 223. 

hastens  disappearance  of  symptoms 

of  primary  syphilis,  122. 

in    .syphilis    in    several    injections 

followed  by  mercury  essential,  123. 

adrenalin  in  conjmiction  with,  304. 

advantage  of  neo-salvarsan  over,  279. 

arsenic  of,  278. 

atoxyl  and  arsacetin  more  toxic  than, 

281. 

auditory  lesions  after.  309. 

blindness  from  use  of,  483. 

blmdness  not  caused  by,  157. 

chemistry  of,  276. 

constitutional  formula,  277. 

contraindications  to,  312. 

• deaths  from,  483. 

decreases  clotting-time  of  syphilitic  sera. 


93. 


discovery  of,  steps  leading  to,  284. 

diseases  following  administration  of,  300. 

effect   on  cerebro-spinal  fluid,  205,  206, 

207. 

on  relapsing  fever,  5. 

on  syphilitic  iritis,  155. 

on  yaws,  5. 

upon  neutrophiles  and  lymphocytes 

in  sj'philis,  150. 

fatal  cases  following,  312. 

formation  of  antibodies  checked  by,  141. 

formula,  when  injected,  280. 

haemorrhagic,  not  due  to  salvarsan,  228. 

haemorrhagic  encephalitis  oecurrmg  inde- 
pendently of,  224. 

Herxheimer's  reaction  after,  303. 

hydrochloride  of,  277. 

in  diagnosis  of  sypliilitic  arthritis,  173. 

in  pulmonary  s^'jihilis,  108. 

in  syphilis  of  pylorus,  175. 


Salvarsan  in  treatment  of  syphilis,  influence 
on  VVassermami  reaction,  108,  109,  110, 
HI. 

must  be  supplemented  by  mercury 

and  iodides,  111. 

increases  amino-acid  content  of  syphilitic 

sera,  93. 

influence  on  protein  content  in  cerebro- 
spinal fluid,  192. 

on  Wassermami  reaction,  ex- 
plained, 93. 

injections  of,  ill  effects  following,  295. 

jaundice  following,  295. 

insufficient  use  of  harmful,  123. 

intervals  in  treatment,  toxic  s^^nptoms 

after,  302. 

intramuscular  injection  of,  337. 

clinical  course  after,  339. 

intravenous  injection  of,  341. 

marriage  permitted  to  men  after  treat- 
ment by,  257. 

neuro-recurrenoes  after,  308. 

no  improvement  under  in  aberrant  form 

of  syphilis,  14,  15. 

not  supplemented  by  mercurv,  harmful, 

123. 

optic  lesions  after,  309. 

original  base  substance  of,  278. 

oxidation  product,  toxic  action  of,  224, 

225. 

positively  acting  serum  becoming  nega- 
tive after  injection  of,  93. 

producing  symptoms  of  cerebral  com- 
pression, 1. 

properties  of,  277. 

provocative  injections  of,  110. 

in  women,  256. 

raises   amino-acid    content   of   syphilitic 

sera,  89. 

reagent  against  Spirochaeta  pallida,  280. 

relationship  between  potency  and  toxicity, 

294. 

second   dose   actmg   as   anaphylotoxine, 

224,  225. 

second   injection   followed   by   death   in 

case  of  basal  meningitis,  234. 

sodium  salt  of,  277. 

successive  injections  of,  effect  on  lipoid 

globulin  molecules,  94. 

syphilitic  anaemia  due  to,  present  rarity, 

150. 

neuritis  of  cranial  nerves  following, 

160. 

therapeutic  action  compared  with  that  of 

salvarsan,  280. 

elaboration,  284. 

author's  views  on,  285. 

toxic  manifestations  in  post-pure  water 

days,  300. 


616 


INDEX. 


Salvarsan,  toxic  symptoms  of,  226,  294,  298. 

toxicity  increased  by  presence  of  patho- 
genic organisms,  299. 

treatment   by,   histological   condition   of 

syphilitic  plasmoma  after,  9.3. 

in  several  injections,  and  followed 

by  prolonged  mercury  treatment,  effects, 
220. 

inadequate  or  spasmodic  checking 

production  of  antibodies,  219. 

Wassermann  reaction  becomes  increas- 
ingly positive  only  after  first  two  or  three 
injections  of,  93. 

water    question   in  preparation  of,  295, 

297. 

and  grey  oil  injections,  effect  on  syphilitic 

deafness,  160. 

and  mercury  combmed  in  treatment  of 

syphilitic  optic  neuritis,  157. 

effect  on  syphilitic  neuritis  of  cranial 

nerves,  100. 

See  also  Neo-salvarsan. 

Salvarsanised  serum,  intrathecal  injection  of, 

346. 

Saprophytic  organisms,  leucocytozoon  de- 
stroyed by,  123. 

Sarcoma,  arishig  in  plasma  cells,  546. 

diagnosis  of  syphilitic  osteoperiostitis  as, 

171. 

part  played  by  lymphocytes  in,  538. 

Sarcomatosis  cutis,  547. 

Scabies,    differentiation     from    syphilis,    142, 
Schaudinn  and  Hoffmann,  discovery  of  Spiro- 

chaeta  pallida,  2. 
Schereschewsky,    mixed   cultivation   of   spiro- 

chaetae,  59. 

See  also  Fornet  and  Schereschewsky. 

Schmidt,  pathlogical  changes  resulting  in  sepa- 
ration of  epiphyses,  265. 

Sohiiffel,  Peripylephlehitis  syphilitica,  269. 

Schukowsky,  Metrorrhagia  neonatorum,  270. 

Sohiirmann,  colour  test  of,  69. 

Sciatic  nerve,  syphilitic  neuritis  of,  231. 

Scrotum,  enlargement  in  late  syphilitic  lym- 
phangitis, 145. 

Sebaceous  adenoma,  518,  524. 

Self-abuse,  sexual  neurasthenia  caused  by, 
478. 

Seminal  vesicles,  inflammation  of,  399. 

massage  of,  400. 

Sensitising  process,  changes  produced  by, 
447. 

Sequeira,  J.  H.,  aberrant  form  of  syphilis  asso- 
ciated with  Diabetes  iiisijiidus,  15,  17. 

Sera,  amphoteric,  73. 

action  of   on   cells  of  syphilitic  bodies, 

44. 

pressure,   plus   and   minus  on,  76. 

active,  use  of,  257. 


Sera,  antigonococcus,  445. 

"  control,"  439. 

effect  on,  by  treatment  with  barium  sul- 
phate, 78. 

fixation  of  complement,  438. 

immune  horse  and  human,  445. 

sensitising  process,  447. 

multiplication  of  bacteria    in,  precaution 

against,  45. 

normal,    differentiation   from    syphilitic, 

difficulties  in,  82. 

effect  of  lecithm-globulm  on,  79. 

lipoid-globulin    particles   in,   prob- 
ably complement,  82. 
surface  tension  in,  96. 

of  pregnant  and  syphilitic  women,  close 

resemblance  between,  95. 

of  syphilitic  non-pregnant  women,  be- 
haviour of,  258. 

syphilitic,  active,  75. 

in  connection  with  pure  com- 
plement fixation  test,  76. 

majority  of  positive  reactions 

obtained  from,  75,  76. 

amino-acid  content,  87,  88. 

and     Wassermann     reaction, 

92. 

diminution,  87,  88. 

increased  by  salvarsan,  93. 

• less  in  untreated  cases,  88. 

•  amount  of  calcium  salts  in,  87. 

clotting-time  decreased  by  sal- 
varsan, 93. 

colloidal  particles  larger  in.  than  in 

normal  sera,  84. 

decrease     of     amino-nitrogen     in, 

92. 

differentiation  from  normal,  82. 

-; dilution  with  saline,  74. 

effect  of  lecithin-globulin  on,  79. 

effect  of  temperature  on,  74. 

on  addition  of  amino-acids  to, 

on  Wassermann  reaction,  92. 

of  heating  on,  75. 

freezing  jioint  of,  75. 

globulin    complexes    increased    in, 

92. 

increase  of  nitrogen  in,  84. 

lipoid-globulin  of  related  to  that  of 

serum  in  women,  258. 
lipoid-globulin  particles  in,  become 

antibody,  82. 

lipoid  nitrogen,  estimation  not  pos- 


sible, 84. 


rapidity  for  clotting,  87. 
substances  depressing,  90,  91. 
substances  raising,  89,  90,  91. 
surface  tension  in,  diminished,  96. 
how  lowered,  78. 


INDEX. 


617 


Sera,  syphilitic,  time  taken  to  become  positive, 
74. 

Sero-diagnosis,  optic,  of  syphilis,  fii). 

Serum  diagnosis  of  syphilis.  See  W'assermann. 
reaction. 

inactivated,  yielding  more  positive  reac- 
tion than  active  serum,  76. 

increase  of  adsorptive  capacity  result,  97. 

of  lipoid  globulin  in,  83. 

mode  of  existence  of  amino-acids  in,  88. 

natural  proteins  in,  only  react  with  trace 

of  nitrogen,  88. 

normal,  salts  in,  effect  on  Wassermann 

reaction,  86. 

of  pregnant  woman,  factor  necessary  to 

break  down  placental  extract,  95. 

of  women,  protective  substances  in,  258. 

salvarsaniscdintrathecalinjcctions  of,  346. 

in  treatment  of  non-degenera- 
tive encephalitis,  214. 

syphilitic,  addition  of  antigen  to  increases 

size  of  ultra-microscopic  particles,  82. 

application  of  controls,  109. 

giving  positive  ninhydrin  reaction 

with  placental  extract,  95. 

giving  positive  ninhydrin  reaction 

in  presence  of  complement,  96. 

inactivation  of,  109. 

lipoid-globulin  in  adsorptive  capa- 
city, 82. 

— positive  becomes  negative  after  in- 
jection of  salvarsan,  93. 

testing  of,  109. 

See  also  Lijioid-globulin  of  serum. 

Serum  reactions,  effect  of  colloidal  and  non- 
colloidal  bodies  on,  77. 

Sexual    connection,    date 

chancre,  after,  125. 
Sexual   desire,   diminution 

generative  myelitis,  247. 
Sexual  function,  477. 

weakness  in  svphilitic  meningo-myelitis, 

242. 

Sexual  neurasthenia,  478,  481. 

Sexual  organs,  female  and  congenital  syphilitic 
diseases  of,  extreme  rarity,  270. 

Sheep's  red  blood  corpuscles,  washing  and 
dilution,  66. 

Shillitoe,  greater  development  of  degenera- 
tive lesions  of  syphilis,  230. 

Shoemakers,  liability  to  osteo-periostitis  of 
sternum,  172. 

Siedlecki.     See  Kryzszlalowicz  and  Siedlecki. 

Siegel,  Cijtorrhyctes  luis,  I. 

Silver  nitrate  impregnation  method,  demon- 
stration of  Spirochaela  pallida  by,  2. 

Silver  nitrate  method,  Levaditi's,  Koguchi's 
modification,  for  demonstration  of  S^iiro- 
chriela  pallida,  in  section,  63,  64. 


of 


appearance    of 
or  loss   of  in  de- 


Silver  preparation,  application  to  spirochaefal 

films,  63. 
Skin,  aleucaemia  of,  546. 

atroph^•  of,  set  uj)  by  maeulo-papules  on 

trunk,  138. 

blood  supply  of  distribution,  141. 

diseases    liable     to     be     confused     with 

syphilis,  412. 

epitheliomata   of,   classification   of,   509, 

512. 

inflammation  of,  relationship  to  malignant 

disease,  509. 

leucaemia  of,  .545. 

lymphocytomata  of,  560. 

syphilitic    infection    of,    compared    with 

lesions  of  nervous  system,  214,  215. 

manifestation  in  severest,  203. 

Skin  eruptions,  syphilitic,  of  generalisation 
stage,  134. 

polymorphic  nature,  136. 

Skin  lesions  of  congenital  syphilis,  262. 
Skull  bones,  gelatinous  atrophy  affecting,  266. 
Smegma,  origin  of,  464. 
"  Snuffles,"  267. 

often  due  to  simple  catarrh,  274. 

Soda.     See  Niideinale. 

Sodium  chloride  solution,  action  on  nuclei  of 
syjAilitic  bodies  and  on  herring's  roe  com- 
pared, 42,  44. 

Sodium  compound  of  salvarsan,  basic  or 
amphoteric  on  injection.  278. 

Sodium  salt  of  salvarsan,  formula,  277. 

Soft  sore.     See  Ulcus  molle. 

Soga.     See  McLeod  and  Soga. 

Soles  of  feet,  rash  in  congenital  syphilis  specially 
affects,  262. 

Sore,  primary,  treatment  of,  321. 

Sjnrmatoct/stitis  gonorrhoica,  399. 

Spermatorrhoea,  481. 

Sphincter  (bladder)  paralysis  in  congenital 
syphilitic  degenerative  myelitis,  271. 

Spinal  cord,  blood-vessels  of,  210. 

injections   of  salvarsanised    serum   into, 

346. 

■ syphilis  of,  cases  diagnosed  as,  215. 

treatment  of,  334. 

syphilitic   degenerative   lesions   occur  in 

any  part  of,  217. 

diseases  of,  content  of  cerebro- 
spinal fluid  in,  195,  196. 

lateral  column  lesions  of,  211. 

lesions  of,  210. 

ameningeal,  243. 

meningeal,  241. 

topographical  anatomy  of,  210. 

Spirochaela  balanitidis,  5. 

Spirochaela  calligi/riim,  relation  to  Spirochaela 
calligyrum  and  <S.  refriiigen-i,  60,  61. 

Spirochaeta,  Gramnegative,  466. 


618 


INDEX. 


Spirochaela  pallida,  485. 

•  ubiquity  of,  in  tissues,  212. 

causes  greatest  histological  change,  121. 

characters  of,  2,  3. 

conditions  of  growth,  under  culture  of 

syphilitic  organism,  17. 

cultivation  of,  59. 

cultures  of  experimental  infection  with 

syphilis  by,  23. 

demonstration  in  section,  63. 

■  by  Noguchi's  modification  of  Leva- 

diti's  silver  nitrate  method,  63,  64. 

■ in  syphilitic  lesions,  2. 

methods,  62. 

development  in  culture,  extra-cellular,  23. 

in  life-cycle  of  Leucocytozoon  sypM- 

9. 

pronounced  in  s\-philitic  degenera- 
tive lesions,  212. 

discovery  of,  2. 

envelope  of,  containing  unsaturated  fatty 

acid,  61. 

extracellular  development,  217. 

■  fertilisation  of  female  gamete  by,  9,  10. 

fixation  by  of  complement  in  presence  of 

antibody,  61. 

in  liver,  269. 

life-history  of,  3,  4,  6. 

lipoid-protem  content  of,  57. 

phases  in  development  of,  61. 

presence  of,  in  diagnosis  of  chancre,  125. 

question  whether  cause  of  syphilis,  3. 

recognition  of,  497. 

relation  to  concept  ional  syphilis,  249. 

salvarsan     and     neo-salvarsan     reagents 

against,  280. 

situation  of,  in  brain,  210. 

•  staming  in  in  vivo,  28,  29. 

Spirochaela  refringens,  demonstration  in  sy])hi- 

litic  material,  2. 
Spirochaetae,  action  of  salvarsan  on,  296. 
treatment  primarily  to  destroy,  122, 

123. 

cultivation,  anaerobic,  method  for,  62. 

■  death  of,  does  not  ensure  destruction  of 

spores,  122. 

•  developed  under  aerobic  and  anaerobic 

conditions,  60. 

developing    extra-eellularly    differ    from 

those  developing  intra-cellularly,  57. 

in  large  mononuclear  leucocytes,  57. 

development  under  aerobic  conditions,  60. 

distinction  by  means  of  morphology,  60. 

extra-oeUular    development    in     human 

ulcerative  chancres,  121. 

hydroxyl  group  of,  305. 

■  increase  in  number  of,  60. 

infective  granule  of,  4. 

long,  extra-cellular  development,  58. 


Spirochaetae,  organs  in  which  found  most 
abundantly  in  congenital  syphilis,  275. 

positive  Wassermann  reaction  does  not 

guarantee  presence  of,  in  body,  97. 

presence  in  inguinal  glands,  121. 

produced   by  spores  in  syphilitic  tissue 

upon  inoculation,  121. 

variations   occasioned   by   conditions   of 

growth,  60. 

Spirochaote  films,  application  of  silver  prepara- 
tion, 63. 

bathmg  with  Huge's  fluid,  03. 

treatment  of,  63. 

Spleen,  enlargement  in  congenital  syphilis,  180, 
270. 

•  early  syphilis,  180. 

— — • ■  in  tertiary  syphilitic  fever,  179. 

lymphocytes  formed  in,  537. 

Spondylitis  deformans,  410. 

Spore  cysts,  asexual  development  of,  56. 

granular  cells,  resembling,  21. 

Spores,  destruction  of,  not  ensured  by  death 

of  spirochaetae,  122. 
inflammation  of  local  blood-vessels  set  up 

by,  123. 

peripheral  spread  of,  122. 

Sporoblast,  definition  of,  10. 
Sporotrichosis,  diagnosis,  143. 
Sporozoitc,  definition  of,  10. 

of  Leucocytozoon  syphilidis,  8. 

Sporozoites,  development  of,  55,  505. 

staining  of  in  vivo,  29. 

Sporozoites  and  small  lymphocytes,  resem- 
blance between  staming  of,  41. 

Staining  capacities  of  living  and  dead  cells, 
difference  between,  26. 

Stainmg  characters  of  lymphooj'tes,  528. 

Staining  methods  for  gonococcus,  371,  373. 

Staming  processes,  importance  of  electrolytes 
in, -26. 

Staining  reagents,  best  methods  for  use  in  %-ital 
staining,  27. 

•  protoplasm  of  syphiUtic  bodies  resistant 

to,  47,  48. 

— ■ —  used  in  micro-chemical  investigations  of 
Leucocytozoon  syphilidis.  25.     See  also  Dyes. 

Stalagmometer,  examination  of  sera  by,  78. 

Stapedius  muscle,  paresis  of  nerve  supplying, 
160. 

Sterilisation  of  vessels,  methods  of,  297. 

Sternum,  osteo  periostitis  of,  liability  of  shoe- 
makers to,  172. 

Stomach,  syphilis  of,  174. 

decrease  of  hydrochloric  acid  con- 
tent in,  175. 

differential    diagnosis    from    other 

diseases,  175,  176. 

Stomatitis,  mercurial,  354. 

Streptobacillus,  culture  of,  360. 


INDEX. 


619 


Streptobacillus,  description  and  staining  of,  359. 

incidence  of,  360. 

of  soft  sore,  358. 

Sugar,  present  in  syphilitic  tissue  cells,  49. 
Suicide  after  contracting  syphilis,  483. 
Sulphur,  adjunct  in  mercurial  treatment,  353. 
Suppositories,  mercurial,  353. 
Suprarenal  capsules,  congenital  syphilitic 

disease  of,  270. 
Surface  tension,  decrease  in  colloidal  solutions, 

how  produced,  96. 
■ in  normal  sera,  96. 

in  sj'philitic  sera,  how  diminished,  96. 

— —  of  syphilitic  sera,  how  lowered,  78. 

and   Wassermaim   reaction,   relationship 

between,  96. 

Synovial  membrane,  commencement  of  syphi- 
litic arthritis  in,  172. 
Syphilide,  congenital,  commonest  form  of,  263. 

macular,  263. 

papular,  263. 

corymbose,  135. 

follicular,  135. 

framboesiform,  137. 

•  papulo-pustular,  differentiation  of  iodide 

rash  from,  143. 

pustular,  263. 

recurrent,  generalised,  not  preceded  by 

chancre-like  sore,  141. 

preceded  by  chancre-like  sore, 

141. 

preceded  by  chancre-like  sore,  case 

of  auto-reinfection,  141. 

rupial,  137. 

seborrhoeic,  137. 

serpiginous,  how  composed,  214. 

squamo-papular,     resembling     psoriasis, 

143. 

syphilides,  annular,  138,  139. 

orbicular,  138. 

recurrent,  138. 

Syphilin,  use  of,  113. 

Syphilis,  aberrant  form  of,  12,  13. 

associated  with  Diabetes  insipidus 

and  xanthoma,  15. 
condition    of    endothelial    cells    in 

case  of,  15,  16. 

• uninfluenced  by  treatment,  12,  13, 

14,  15. 

acquired,  perichondritis  of  nose  in,  105. 

active  positive  Wassermann  reaction  not 

necessarily  indicative  of,  97. 

and    Lupus    vulgaris,    differentiation    of 

facial  scars  arising  from,  140. 

and  marriage,  485. 

ante-natal,  national  loss  by,  250. 

as  cause  of  elephantiasis,  145,  146. 

association  of  Raynaud's   disease  with, 

149,  150. 


Syphilis,  blood  changes  in,  150,  151. 

cause  of  leucaemie  and  aleucacmic  lym- 

phocytomata,  151. 

• cause  of  pernicious  anaemia,  151. 

causing  Erythema  nodosum  and  E.  multi- 
forme, 142. 

cerebro-spinal,     albumin     and     globulin 

content  in  cerebro-spinal  fluid  in,  189. 

■ — ■ —  total  nitrogen  in  cerebro-spinal  fluid 

in,  192. 

changes  affecting  tongue  in,  163,  164. 

■ complicated  by  other  diseases,  100. 

conceptional,  frequency,  256. 

mode  and  cause  of,  249. 

Spirochaeta  pallida  in  relation  to, 

249. 

Wassermann  reaction  in,  103. 

when  recognised,  248. 

congenital,  260,  274. 

alopecia  in,  264.  » 

and  rickets,  266. 

aortic     aneurysm     in    subject    of, 

148. 
appearance  of  embryonic  areas  in 

body  in,  274. 
arthritis  simulating  tubercular  joint 

in,  267. 
association    of    Diabetes    insipidus 

with,  17. 

of  epUepsy  with,  272. 

of  idiocy  with,  272. 

causing     chronic    bilateral    hydra- 

throses,  267. 
• ■  Diabetes   insipidus   with    lesion    in 

pituitary  body,  272. 

diagnosis,  274. 

by  lung  tissue  extract,  115. 

too  often  made,  274. 

diagnostic  sign  of,  262. 

enlargement  of  lymphatic  glands  in, 

273. 

of  spleen  in,  180. 

general  pathology,  274. 

hydrocephalus  in,  266. 

interstitial  keratitis  in,  156. 

organs   in   which   spirochaetac   are 

found  most  abimdantly  in,  275. 
phases   of  Leucoci/tozoon   st/philidis 

found  in  various  organs  in,  275. 

prognosis,  274. 

pupil  anomalies  in,  272. 

• • purpura  in,  264. 

severer  than  acquired,  260. 

signs  pathognomonic  of,  274. 

■ skin  lesions  of,  262. 

symptoms,  261. 

syphilitic  infection  after  birth  mis- 
taken for,  260. 
treatment  of,  326. 


620 


INDEX. 


Syphilis,  congenital,  Wassermann  reaction  in, 
"results,  variable,  103,  104. 

course,  after  papulo-erosive  and  papulo- 

ulcerative  chancres  compared,  130. 

cure  under  treatment  in  late  stages  im- 
possible for  most  part.  111. 

in  primary  and  generalisation  stages 

possible.  111. 

diagnosis  of,  493. 

by  anti-reaction.     See  also  Lnietin. 

by  colour  test,  69. 

by  cutireaction,  113. 

by  luetin  reaction,  113,  114. 

by  perforation  of  palate,  266. 

by  precipitation  test,  69. 

— — •  diseases  due  to,  most  positive  Wasser- 
mann reaction  seen  in,  80,  97. 

early,  enlargement  of  spleen  in,  180. 

early   lesions    more    infectious   than   re- 
current, 123. 

effect  of  repeated  pregnancy  on,  103. 

errors   of     development    in   relation   to, 

261. 

experimental  infection  from  cultures  of 

Spirochaeta  pallida,  23. 
primary  chancres  of,  tendency  to 

ulcerate,  120. 
•  followed  by  Meniere's  symptom-complex, 

161. 

generalisation  stage,  134,  487. 

of  so-called  albuminuria  in,  84. 

treatment  during  does  not  guarantee 

cure,  222,  227. 

must  be  begun  early  in, 

221,  227. 

human  and  experimental,  changes  in  in- 
guinal lymphatic  glands  compared,  121. 

clinical    ditferences    between,    120, 

121. 
■■  immunity  to,  diminished  by  formation  of 

antibodies,  142. 

in  utero  manifestations  of,  261. 

in  women,  248. 

treatment  of,  324. 

incidence  of,  statistics,  496. 

increase  of  lipoid  in  late  cases  of,  84. 

incubation  period,  119. 

infective  agent  of,  126. 

influence  on  pulmonary  tuberculo.sis,  167. 

initial  stage,  134. 

inoculation  of  apes  with,  first  discovery,  1. 

intestine,   affecting   tissue   subjacent   to 

peritoneum,  176. 

invasion  of  body  by,  followed  by  increase 

of  mononuclear  leucocytes,  83. 

late,  globulinuria  in,  153. 

— lesions  of,  how  differing  from  early, 

85. 

latent  stage,  122,  134. 


Syphilis,  latent  stages,  result  of  Wassermann 
reaction  during,  as  influencing  prognosis, 
221. 

lesions  of,  demonstration  of  Spirochaela 

pallida  in,  2. 

leucoplakia  of  tongue  common  in,  163. 

lipoid  portion  of  lipoid-globulin  molecule 

greater  in  late  cases  of,  94. 

lymphocytes  source  of  protective  sub- 
stances agamst  in  host,  151. 

neuro-recurrences  of,  307. 

■  not   excluded   by  negative   Wassermann 

reaction,  97,  100. 

of  abdominal  viscera,  174. 

-  of  bladder,  153,  154. 

of  bones  and  joints,  169. 

of  bronchi,  166. 

— —  of  eyes,  155. 
■  of  lungs,  166,  167. 

of  lympho-  and  haemopoetic  systems,  144. 

of  male  genito-urinary  tract,  152. 

of  mouth  and  throat,  162. 

of  nervous  system  treatment  of,  328. 

of  testicles,  154. 

organism  causing,  question  as  to,  3. 

historj-,  1. 

bibliography,  6. 

life-cycle,  8.     See  also  Leucocylozooti 

syphilidis. 

positive  Wassermann  reactions  in  patients 

who  have  not  had,  98. 

jiredisposing  cause  of  RaJ^laud's  disease 

in  adult,  150. 

primarv,  abandonment  of  term  suggested, 

134. 

biology  of,  119. 

diagnosis  by  clinical  methods  essen- 
tial, 124. 

•  symptoms  of,  disappearance   after 

administration  of  mercury  or  salvarsan,  122. 

■  prognosis  from  lymphocyte  chart,  151. 

■  — - —  study  of  chancres  a  guide  to,  129. 

protective  power  of  host  against,  some- 
times marked,  220. 

protective  substances  against,  97,  98,  258. 

circulating  in  blood,  218. 

in  cerebro-spmal  fluid,  218. 

reagin  a  lipoid-globulin  in  all  cases  of,  61. 

recurrent,  defined,  122. 

diagnosis  by  lung  tissuoextract,  115. 

late,   giving    positive   Wassermann 

reaction,  115. 

recurrent  stage,  134. 

secondary  abandonment  of  term  sug- 
gested, 134. 

skin  diseases  liable  to  be  confused  with, 

142. 

spasmodic  haemoglobinuria  due  to,  150. 

spontaneous  cure  of,  222. 


INDEX. 


621 


Syphilis,  stage  at  wliich  nervous  system  be- 
comes involved,  200. 

tertiary,  abandonment  of  terra  suggested, 

134. 

transmission    of,    not    comparalile    with 

that  of  malaria,  24. 

treatment  of,  321,  491). 

■  assists  host's  resistance,  286. 

by  salvarsan  in  several  injections 

followed  by  mercury,  essential,  123. 
date  of,  influencing  issue  of  Wasser- 

mann  reaction,  102,  105. 
destroys  parasites  indirectly,  286. 

various  stages.  Interpretation  of  positive 

and  negative  Wassermann  reaction  according 
to,  101.  See  also  under  Wassermann  reac- 
tion in  syphilis. 

vascular  lesions  common  in,  123. 

virus  of  not  a  filter-passer,  1. 

Wassermaiui  reaction  m,   as  influenced 

by  treatment,  105-112. 

■ •  stronger  in  late  than  in  earlv  cases, 

85. 
■ •n'hv  less  severe  in  women  than  in  men, 

151. 

with   recurrent    symptoms,   spontaneous 

cure,  111. 

worst    cases    arise    from    papulo-erosive 

chancre,  129. 

Syphilis  d'embUe,  130,  132. 

Syphilitic  and  pregnant  women,  sera  of  close 
resemblance  between,  95. 

Syphilitic  bodies,  amino-acids  in  free  state  non- 
existent in,  38. 

carbohydrates  not  found  in,  48. 

cells  of,  extraction  of  electrolvtes  from, 

40,  41. 

characters  when  stained  in  fixed  speci- 
mens, 30. 

in  vivo,  27. 

— ■ —  connective  tissue,  distinction  from  endo- 
thelial cells  with  circular  masses,  22. 

nuclei  of,  action  of  reagents  on,  42. 

chemical  substance  of,  42. 

tested    by   that   on   herring's    roe, 

42,  43. 

—. reducing  agent  in  stauiing,  34,  35,  37. 

staining  of,  41,  46. 

for  content  in  iron,  47. 

for  content  in  phosphorus,  46, 


47. 


protein  of,  39. 

protoplasmic  portion  of,  38. 

protoplasm  of,  resistant  to  reagents,  47, 

48. 

strongly  pyio^inophile,  48. 

pyroninophile  substance  of,  49,  52. 

reducing    substance,   action    not    depen- 
dent on  tyrosine,  38. 


Syphilitic    bodies,  spore  cysts  of,  red  bodies 
seen  in,  43. 

stauiing  of,  50,  51. 

in  vivo  by  borax  methylene  blue,  28. 

with  pyronin,  31, 

S.vphilitio    cells,    appearance    under    use     of 

Nicol's  prisms,  49. 

reducing  action,  48. 

Syphilitic  extracts,  effect  of  several  injections 

'of,  118. 
Syphilitic     fever,     accompanied     by     liaemo- 

globinuria,  178. 

tertiarj-,  178. 

diseases  mistaken  for,  178. 

enlargement  of  spleen  in,  179. 

rapidly     yields     to     anti-syphilitic 

treatment,  178. 
Syphilitic  infection,  stages  of,  120. 
Syphilitic  lesions,  experimental  production  by 

culture  of  spirochaetae  produced  aerobically 

as  well  as  anaerobically,  CO. 

simulated  by  syphilitic  cutireact  ions,  116. 

Syphilitic  material  examination  of,  errors  to  be 

a\'oicled  in,  21. 
Syphilitic  neurasthenia,  480,  482. 
Syphilitic  organisms,  accompaniment  l.iy  cocci, 

result,  145. 

process  of  development  in  skin,  135. 

protective  agency  against,  285. 

protoplasm    of    nucleus,    basophilic    and 

partially  acidophic,  31. 

pyroninophile  substance  of,  31,  49,  52. 

sections    of,    substances    used    for    pre- 
serving, 33. 

staining  of,  31. 

clearing  fluids  for,  33. 

electrolj'tic  theory  of,  31. 

fixing  reagents  employed,  31,  32. 

tissue  cells  of,  contaui  sugar,  49. 

Syphilitic    tissues,    staining    of    alcohol-fixed 

specimens,  51. 

— — ■  — paraffin  sections,  51. 

Syphilitic,  triad,  273. 

Syphilitics,    congenital,    propagating   syphilis, 

261. 
S/jphilomt/ces,  discovery  of,  1. 
Syringe,  McDonagh's  intravenous,  343. 
Syringes,  intravenous,  Luer's  and  Schreiber's, 

"  342,  343. 
SyringoepitheUoma,  511. 
Syringoma,  517,  519. 
Tabes  donalis  as  lymphogenous  infection,  209. 

term  replaced   by  that   of  degenerative 

myelitis,  244. 

Tedeschi,   first   use   of   cuti-   and   ophthalmo- 
reaction in  syphilis,  113. 
Teeth,  congenital  syphilitic  affections  of,  204. 

primary,    occasionally    affected    in    con- 
genital syphilis,  264. 


622 


INDEX. 


Temperature,  effect  upon  syphilitic  sera.,  74,  75. 
Teiido  achilhs,  insensibilitj'  of,  in  degenerative 

myelitis,  247. 
Tendons,  syphilitic  lesions  of,  173. 
TenosjTiovitis,  gonococcal,  406. 
Testicles,  congenital  syphilitic  disease  of,  270. 

syphilis  of,  154. 

Tetranitro  chrysoplianic  acid,  nature  of,  37. 

staining  of  sections  of  syphilitic  bodies 

with,  37. 

Tetravalent  elements,  726. 

Thoma-Zeiss  haemooytometer,  185. 

Throat,  syphilis  of,  162. 

Thymus,  Dubois's  abscesses  of,  270. 

Tibiae,  nodes  on,  in  double  interstitial  keratitis, 
273. 

■ periostitis  of,  in   later  life  diagnostic  of 

congenital  syphilis,  274. 

Tiodine,  use  of,  476. 

Tissue  basophile,  583. 

Tissues,  chief  classes  of  bodies  in.  37. 

Toluol,  sterilising  agent,  297. 

Tongue,  effect  of  oral,  administration  of  mer- 
cury on,  163. 

inflammatory      changes      produced      by 

syphilis,  163,  164. 

becoming  malignant,  164. 

factors  keeping  up,  163. 

leucoplakia  of,  163. 

Tonsil,  gumma  of,  164,  165. 
— ■ — •  primary  chancre  of,  164. 

Tonsillitis,    follicular,    diagnosis    of    primary 

chancre  of  tonsil  from,  164. 
Toxic  manifestations  in  pre-pure  water  daj-s, 

298. 

•  in  post-pure  water  days,  300. 

Toxic  rashes,  425. 

Toxicity  of  salvarsan  increased  by  presence  of 

combination  of  organisms,  299. 

relationship    between    potency    and,    of 

salvarsan,  294. 

salvarsan,  increased  by  presence  of  patho- 
genic organisms,  299. 

Trapezius  muscle,  injection  of  salvarsan  into, 
338. 

Trauma  in  relation  to  sypliilitio  bone  lesions, 
172. 

Traumatic  lesion,  diagnosis  of  chancre  from, 
133. 

Treatment,  drugs  used  and  methods  of  ad- 
ministering them,  337. 

of  brain  syphilis,  328. 

of  congenital  syphilis,  326. 

of  encephalitis,  331,  333. 

of  generalisation  stage,  323. 

of  gumma,  330. 

of  latent  stage,  324. 

• of  primary  sore,  321. 

• of  recurrent  stage,  322. 


Treatment  of  spinal  syphilis,  334. 

of  sj'philis,  321, '496. 

in  women,  324. 

tabulation  of,  322. 

Trichoepithelioma,  511. 
Trichoepithelioma  papillosum,  515. 
Triglyceride   emulsions   in   sera   give    marked 

positive  Wassennann  reactions,  90. 
Triglycerides,  anti-complementary  action  of,  80. 
depress  amino-acid  content  of  syphilitic 

sera,  90. 

give  rise  to  positive  reaction,  93. 

Trivalent  elements,  276. 

Trophic  disturbances  in  degenerative  myelitis, 

245. 
Trophozoite,  19. 

definition  of,  10. 

development    into  asexual  spore  cvsts, 

56. 

into  male  and  female  bodies,  con- 
ditions for,  56. 

•  ■  into  sexual  merozoites,  56. 

mode  of,  on  what  dependent,  56. 

Trypanosomes,  inf ecti  ve  granule  of ,  4. 

rendered  arsenic -fast,  284. 

Tubercular  joint,  arthritis  simulating  con- 
genital sj-philis,  267. 

Tubercular  osteom3'elitis,  diagnosis  from  sy- 
pliilitic,  172. 

Tuberculides,  difficult,  how  to  diagnose.  143. 

Tuberculin,  injection  in  sj^hilitic  case  followed 
by  injection  of  pallidm,  117. 

Tuberculosis,  pulmonary,  diagnosis  from  sy- 
philitic disease,  167. 

influence  of  syphilis  on,  167. 

little  influenced  by  syphilitic  treat- 
ment, 167. 

Tuberculous  ulcers,  diagnosis  from  female 
chancre,  254. 

Tumor alhn<,  late  manifestation  of  syphilis,  173. 

Tumours,  mixed,  519. 

origins  of,  511.  524. 

Trypanosomiasis,  positive  Wassermann  reac- 
tion in,  100. 

Tyrosine,    reducing    substance    of    syphilitic 

bodies  not  dependent  on,  38. 
Tyson's  glands,  464. 
Ulcera     gangrenosa,     diagnosis    from     Ulcera 

pseudo-venerea,  255. 

organisms  living  in  sjTnbiosis  in,  255. 

Ulcera  pseudo-venerea,  254. 

bacillus  of,  254. 

diagnosis  from  syphilitic  sores,  254. 

■ symptoms  and  characters  of,  254. 

Ulcers,  Balanitis  erosiva,  causing,  465. 
Ulcus  Uennorrhagiciim,  424. 

Ulcus  molle,  11,  3f  8. 

auto-inoculable,  2.54. 

bubo  following,  358,  366. 


INDEX. 


623 


Ulcus  mulle,  chancre  developed  from,  361. 

diagnosis  of  chancre  from,  133. 

diagnosis  of  femiile  chancre  from,  2.54. 

Ducrey's  bacillus,  extra-cellular  in,  367. 

female,  diagnosis  of  pseudo-membranous 

chancre  from,  252. 

mixed  infection  of  female  chancre  with, 

253. 

primary  sore  developing  on,  133. 

(soft  sore),  358. 

treatment  of,  308. 

Ulcus  molle  elevriliim,  361. 
Ulcus  molle  miliare,  361. 

Ulcus  molle  phagednenicum,  362. 
Ulcus  molle  serpiginosiini,  11,  362,  470. 

amino-plasma  cells  met  with  in,  36. 

Iiacteriology  of,  366. 

cases  illustrating,  364. 

clinical  description,  363. 

treatment  of,  365,  36S. 

Ulcus  rodens,  514. 

Ultra-microscopic  particles  increased  in  size 
by  addition  of  antigen  to  syphilitic  serum,  82. 

Ultzmann's  syringe,  use  of  in  treatment  of 
prostatitis,  396. 

Unguenlum-  iode.v,  external  administration  in 
case  of  Coccidiosis  avenerea,  19. 

Unna,  action  of  rongalit  white,  30. 

classification  of  alliumoses,  38. 

hyaline  plasma  cell  of,  35. 

Unna's  hyaline  masses,  502. 

Unna's  theory  of  reduction  and  oxidation,  31. 
Urethra,  condylomata  of,  468. 

endoscopic  examination  of,  379. 

gonorrhoeal  infection  of,  377. 

male,  anatomy  of,  375. 

See     also      Chancre,     primary,     intra- 

urethral. 

Urethritis,  acute,  treatment  of,  382,  386. 

anterior,  385. 

— ■ —  chronic,  378. 

nature  of  discharge  in,  381. 

secondary  infection  in,  380. 

gonorrhoeal,  376. 

complications  of,  388. 

goiiorrhoica,  403. 

in  female,  428. 

non-gonococcal,  causes  of,  416,  418. 

inclusion  bodies  observed  in,  418. 

posterior,  treatment  of,  383. 

subacute,  386. 

treatment  of,  390,  452. 

Urethroscope,  Wossidlo's,  379. 

Urine,  condition  of  in  gonorrhoea,  377. 

effect  of  mercury  on  globulin  excretion  in, 

152. 

lipoid-globulin  in,  153. 

method  of  examination  for  protein.  152, 

153. 


Urine,  protein  in,  in  acute  stage  of  syphilis,  152. 

yielding   positive   Wassermann  reaction, 

85. 

Urobilinuria  in  syphilitic  hepatitis,  178. 
Uterus,  gonococcal  infection  of,  431. 
Vaccine  treatment,  methods  employed,  441. 
Vaccines,  effect  on  gonorrhoeal  iritis,  155. 
on  patients'  scrum,  444. 

gonococcal,    in    treatment    of    Arthritis 

defortna II sioMowing  gonorrhoea  and  syphilis, 
173. 

intravenous  injections  of,  443. 

subcutaneous  injections  of,  441. 

sensitised  in  epididymitis,  403,  4.53. 

in  gonorrhoea,  444. 

therapeutic  effects  of,  441,  450. 

Vagina,  chancre  of,  253. 

secretions  of,  428. 

Vaginitis,  gonococcal,  430,  432. 

Van  Buren's  disease  (Iiiduralio  penis  plaslica), 

474. 
Van  Slyke,  gasometric  estimation  of  primary 

alephatic  amino-nitrogen,  87. 
Van  Slyke's  method  for  testing  antigen,  71. 
Varicella,  distinction  of  syphilitic  pustule  from, 

136. 
Varicocele,  478. 

Fas  deferens,  gonococcal  infection  of,  400. 
Vascular  lesions,  cause  of  headache,  238. 
Vascular  system,  congenital  syphilitic  disease 

of,  267.  ' 
Veins,  congenital  syphilitic  disease  of,  267. 

injections   into,   advantages   over  intra- 
muscular injections,  34.5. 

Venereal  disease  and  marriage,  485. 

and  Public  Health,  493. 

Venereal  diseases  in  the  Services,  405. 

Venous  lesions,  primary  syphilitic,  dependence 

of  syphilitic  affections  of  nerve  tissue  on, 

212." 
Vesiculitis  gonorrhoica,  399. 
Vlbro-shapcd  organisms,  Grampositive,  466. 
Virchow,  congenital  syphilitic  disease  of  supra- 

renals,  270. 

white  pneumonia  of,  268. 

Virus,      syphilitic,      affects      organ,      before 

maturit}-,  274. 
Vital  staining,  best  method  for  use  of  reagents 

in,  27. 
Vulva,  antiseptic  washes  for,  432. 
Vulvitis,  acute,  causes  of,  464,  466. 

treatment  of,  429,  432. 

erosiva  et  gangrenosa,  254. 

Vitlvo  vaginitis  in  children,  429,  434. 
Warts,  venereal,  467. 

Wassermann   and   Bruck,   serum   diagnosis  of 
sj'philis,  69.     See  also  Wassermann  reaction. 

and  Lange,  origin  of  reagin  substance  in 

cerebro-spinal  fluid,  78. 

2   R 


624 


INDEX. 


Wasscrniann  reaction  and  Abderhalden's  test, 
comparison  between,  98. 

and    amino-acid    content    of    serum,    no 

direct  ratio  between,  92. 

and  surface  tension  relationship  between, 

96. 

antigen   neither   specific    nor   absolutely 

necessary  for,  73. 

becomes  increasingly  positive  only  after 

first  injections  of  salvarsan,  93. 

complement   most  important   factor  in, 

98. 

effect  of  addition  of  amino-acid  to  sera 

on,  92. 

of  salts  in  normal  serum  on,  86. 

enormous  increase  in  cerebrospinal  fluid, 

just  before  death,  192. 

factors  concerned  in,  71. 

in  cerebro-spinal  fluid,  193. 

in  degenerative  encephalitis,  196. 

in  degenerative  myelitis,  196. 

information  given  by,  193. 

in  conceptional  syphilis,  103. 

in  congenital  syphilis,  103,  104. 

degenerative  myelitis,  245. 

— —  in  differential  diagnosis,  104. 

in  Mycosis  fungoides,  558. 

in    women,    if    positive,    indication    for 

contmuous  treatment    during  child-bearing 

period,  256. 
— —  in  svphilis  as  influenced  by  treatment, 

105-112. 
results  paradoxical,  107,  108, 

111,  112. 
in  latent  stage,  positive  or  negative 

according  to  various  factors,  101,  102. 
in     recurrent     stage,     positive     or 

negative,  101. 
in  stage  of  generalisation  of  virus, 

positive,  101. 

■ of  initial  lesion,  negative,  101. 

in  women,  results,  103. 

when  positive  and  when  nega- 
tive, 249. 
of  nervous  system,  104. 

in    syphilitic    child    becoming    positive, 

275. 

in  women,  256. 

influence  of  salvarsan  on,  explained,  93. 

influencmg  development  of  degenerative 

lesions  of  nervous  system,  221. 

— —  marked     positive   given    by   triglyceride 
emulsions  in  sera,  90. 

modifications  of,  70,  98. 

increase  incidence  of  positive  reac- 
tions in  those  who  have  not  had  syphilis,  100. 

most   positive,   obtained   from    cases   of 

disease   due  to  syphilis,  97. 

negative  after  injection  of  serum,  347. 


Wassermann  reaction  negative  after  treatment 
no  indication  as  to  parasites  killed  or  left,  94. 

does  not  exclude  syphilis,  100. 

does     not     exclude     syphilis,      or 

indicate  cure,  97. 

with  decrease  of  globulin  in  cerebro- 
spinal fluid,  191. 

not  sjjecific,  94. 

persistence  in  cerebro-sjiinal  fluid,  196. 

positive,  after  application  of  cutaneous 

test,  in  late  recurrent  syphilis,  115. 

factors  responsible  for,  97. 

■ in   blood   in   degenerative   myelitis 

and  encephalitis,  explanation,  218. 
in  blood  taken  just  before  or  just 

after  death  in  non-syphilitic  cases,  85,  86. 

in  diseases  other  than  syphilis,  100. 

in    patients    who    have    not    had 

syphilis,  98. 
not  necessarily  indicative  of  active 

syphilis,  97. 

under  influence  of  triglycerides,  93. 

very  strong  in   case   of  cutaneous 

lymphocytoma,  signiflcance,  97. 

without  active  syphilis,  486. 

yielded  by  urine,  85. 

positive  or  negative  during  latent  stage 

as  influencing  prognosis,  221. 

positivity  and  oxydase  content,  no  ratio 

between,  98. 

precipitation  theory  of,  96. 

process  of  pure  precipitation,  96. 

rationale  of,  69,  71. 

reagin  in,  source  of,  151. 

relation  of  total  nitrogen  in  cerebro-spinal 

fluid  to,  192,  193. 

sharpening  of,  73,  74. 

significance,  100-105. 

.source  of  reagin  in  cerebro-spinal  fluid, 

193. 

strong  accompanying  lipoid  degeneration 

in  syphilitic  aortitis,  148. 

stronger  in  late  than  in  early  syphilis,  85. 

• substances  necessary  to  jiroduce  fixation 

in,  73. 

technique  of,  65-68. 

attempts  at  simplification,  70. 

original  form  alone  reliable,  98,  100. 

use  of  natural  complement  in,  70. 

Water,  distilled,  contaminated,  eft'ccts  of,  296. 

methods  of  special  preparation,  297. 

protein  of  syphilitic  bodies  insoluble  in, 

39. 

salvarsan   preparation   and   question   of, 

295,  297. 

toxic    manifestation    in    pre-pure    water 

days,  298. 

in  post-pure  water  days,  300. 

Wax,  use  of,  in  fixing  syphilitic  specimens,  32. 


INDEX. 


625 


Wechsclmann's  modification  of  Wassemiann's 

reaction,  70. 
— —  precipitation   of   complementoid   bodies, 

70. 
Wechselmann's  barium  sulphate  modification, 

77. 
Wegner's  Osleochondrilis  si/pltilitica,  26.5. 
VVeygandt  and  Jakob,  experimental  evidence 

on   sj'philitic    disease    of    nervous  system. 

229. 
•  route    of    syphilitic    infection    of 

central  nervous  system,  207,  208. 
Widal  reaction,  negative,  significance,  100. 

positive,  given  by  Vlcera  pseudo-venerea, 

254. 

Wife,    syijhilitie    infection    of    and    marriage 

question,  489. 
Wimmer,    Prof.,    increase    of    percentage    of 

nervous  lesions  of  syphilis,  230. 
Women,  child-bearing,   symptoms   of  syphilis 

mild  in,  257. 

gonorrhoea  in,  complications  of,  428. 

course  of,  428. 

origins  of  extra-genital,  427. 

symptoms  of,  431. 

treatment  of,  432. 

gonorrhoeal  infection  without  symptoms 

in,  491. 

reason  why  syphilis  less  severe  in  women 

than  in  men,  151. 

recurrences  of  syphilis  fewer  and  milder 

in,  257. 


Women,  seruui    of,  lipoid-globulin   related   to 

that  of  syphilitic  sera,  258. 
protective  substances  in,  258. 

syphilis  in,  248,  490. 

generalised,  2.55. 

not  so  serious  as  in  men,  257. 

results  of  Wasscrmann  reaction,  103. 

treatment  of,  324. 

during  pregnancies  succeeding 

birth  of  syphilitic  iniant,  2.')0. 

Wassermann  reaction  in,  when  posi- 
tive and  when  negative,  249. 

syphilitic  arterial  lesions  in,  257. 

non-pregnant,  behaviour  of,  258. 

Wassermann  reaction  in,  256. 

Women  and  men,  difference  between  sjrphilis 

in,  257. 
• no  difference  in  primary  lesions  of  syphilis 

between,  257. 
Wossidlo's  urethroscope,  379. 
Xanthelasma,  564. 
Xanthoma,  564. 

aberrant  form   of  syphilis  and  Diabetes 

insipidus  associated  with,  15,  17. 

Xanthoma  tuberosum,  572. 
Xanthoiiiartiger  naents  i^ermcosus,  572. 
X-rays   in   diagnosis   of   syphilitic   disease   of 

huigs,  168. 
Yaws,  effect  of  salvarsan  on,  5. 
Zygote,  cells  resembling,  21. 

definition  of,  10. 

development  of,  17. 


LONDON  : 
HARRISOS     AND     SONS,     ST.     MARTIs's     LANE,     \V. 
PRINTERS    IX    ORDINARY   TO    HIS    MAJESTY. 


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